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Breast Cancer Research and Treatment

, Volume 167, Issue 1, pp 9–29 | Cite as

Molecular profile of atypical hyperplasia of the breast

  • David N. Danforth
Open Access
Review
  • 882 Downloads

Abstract

Purpose

Atypical ductal and atypical lobular hyperplasia (AH) of the breast are important proliferative lesions which are associated with a significantly increased risk for breast cancer. The breast cancer which develops in association with AH may occur synchronously, representing local progression, or metachronously at a later date in either the ipsilateral or contralateral breast. These high-risk characteristics of AH suggest they contain significant genomic changes.

Methods

To define the genomic changes in AH, a comprehensive review of the literature was conducted to identify the numerical chromosomal and structural chromosomal changes, DNA methylation, and gene expression abnormalities in atypical ductal and atypical lobular hyperplasia.

Results

AHs are characterized by advanced genomic changes including aneuploidy, loss of heterozygosity, gross chromosomal rearrangements such as amplifications and large-scale deletions, DNA methylation of tumor suppressor and other genes, and gene expression differences between AH and surrounding normal breast tissue including significant estrogen receptor expression. Many of these changes are shared by an associated synchronous breast cancer, consistent with an important precursor role for AH. At the same time, many of the genomic changes of AHs are also shared by common sporadic breast cancer, consistent with a high risk for future development of metachronous breast cancer.

Conclusions

This molecular profile should help clarify the genomic characteristics and malignant predisposition of AH, and aid in the identification of new targets for the prevention of breast cancer

Keywords

Atypical hyperplasia Atypical ductal Atypical lobular Breast high risk Breast cancer Breast carcinogenesis Premalignant breast 

Abbreviations

ALH

Atypical lobular hyperplasia

ADH

Atypical ductal hyperplasia

AH

Atypical hyperplasia

AI

Allelic imbalance

CGH

Comparative genomic hybridization

DIALH

Ductal involvement by cells of atypical lobular hyperplasia

DCIS

Ductal carcinoma in situ

ER

Estrogen receptor

FISH

Fluorescent in situ hybridization

IDC

Invasive ductal carcinoma

IHC

Immunohistochemistry

LCIS

Lobular carcinoma in situ

LOH

Loss of heterozygosity

MSI

Microsatellite instability

MSP

Methylation-specific PCR

NABT

Normal adjacent breast tissue

NSABP

National Surgical Adjuvant Breast and Bowel Project

PDWA

Poorly differentiated without atypia

UDH

Usual ductal hyperplasia

Background

Atypical lobular (ALH) and atypical ductal (ADH) hyperplasia are proliferative lesions of the breast which are associated with a significantly increased risk for breast cancer. The histologic characteristics of these lesions are well defined [1, 2], and ADH and ALH each contain early changes of, respectively, DCIS and LCIS, increasing the likelihood that they will contain at least the early genomic changes of malignancy. Estrogen is a major carcinogen for breast cancer, with the ability to cause single base substitutions, single and double DNA strand breaks, and chromosomal rearrangements [3]. ADH and ALH [collectively atypical hyperplasia (AH)] occur more commonly in women over the age of 55 [4, 5]. This allows for a significant (40 plus year) exposure to estrogens and the potential for widespread genomic damage. Individual reports have described the presence of aneuploidy [6], chromosomal gains and losses [7], DNA methylation [8], and gene expression changes [9] in AH lesions, consistent with this exposure. A comprehensive understanding of these genomic changes is needed to further define the nature and spectrum of these genomic alterations and the relationship of these changes to breast cancer.

Atypical ductal and atypical lobular hyperplasia may be associated with the development of synchronous or metachronous breast cancer. Synchronous breast cancer occurs concomitantly with AH and is considered to represent local progression of AH. The incidence of synchronous carcinoma with AH is, on average, 22.0% (Table 1). For this reason, AH lesions are frequently excised at the time of presentation to include these tumors, which provides an important opportunity to define the genomic characteristics of AH and its associated breast cancer. Interestingly, there appears to be a subset of ALH (lesions which are pure ALH, demonstrating radiographic–pathologic concordance and no associated high-risk lesions found on core needle biopsy) in which the incidence of synchronous carcinoma is low (≤3%; [10, 11]). Metachronous breast cancer develops subsequent to the initial AH, potentially out 25 years or more [5], and may occur in either breast (Table 2). Whereas synchronous breast cancer is more commonly DCIS (Table 1), metachronous breast cancers are more often invasive carcinoma (Table 2), suggesting a range of carcinogenic influences for the genomic changes in AH. Atypical hyperplasias are commonly estrogen receptor positive [12], and treatment with antiestrogens may prevent the development of metachronous breast cancer within the remaining normal breast tissue [13]. This indicates that at least one important molecular characteristic of AH (ER positivity) is an indicator of the responsiveness of the remaining normal tissue to systemic therapy. An understanding of the molecular characteristics of these high-risk lesions may therefore clarify the role of AH in breast carcinogenesis, as well as to promote identification of new targets for the development of drugs for breast cancer prevention.
Table 1

Incidence and characteristics of synchronous carcinoma with atypical hyperplasia

Primary atypical hyperplasia

Number of AH cases excised

Overall carcinoma

Invasive carcinoma

Ductal carcinoma in situ

Risk factors

References

ADH

62 cases

9 cases (14.5%)

2 cases (3.2%)

7 cases (11.3%)

Personal/family history breast cancer

[60]

ALH

73

13 (17.8%)

5 (6.8%)

8 (11.0%)

 

[61]

ADH

104

22 (21.2%)

3 (2.9%)

19 (18.3%)

 

[62]

ADH

76

21 (27.6%)

3 (3.9%)

18 (23.7%)

 

[63]

ADH

61

19 (31.2%)

5 (8.2%)

14 ((23.0%)

 

[64]

ALH

97

21 (21.6%)

6 (6.2%)

15 (15.5%)

 

[65]

ADH (9 gauge)

74

16 (21.6%)

2 (2.7%)

14 (18.9%)

 

[66]

ADH

101

20 (19.8%)

3 (3.0%)

17 (16.8%)

Number of ADH foci

[67]

ADH

65

11 (16.9%)

5 (7.7%)

6 (9.2%)

Increasing age

[68]

ALH

40

11 (27.5%)

4 (10.0%)

7 (17.5%)

 

[69]

Mean

 

21.97% ± 1.7

5.47% ± 0.84

16.52% ± 1.55

  
Table 2

Risk and incidence of metachronous breast carcinoma with atypical hyperplasia

Type of atypical hyperplasia

Number of cases

Follow-up

Overall carcinoma

Invasive carcinoma

DCIS

Relative risk

References

AH

331

Mean—13.7 years

18.4%

16.0%

2.4%

Overall—3.88

ALH—3.67

ADH—3.83

ALH + ADH—7.10

[4]

AH

668

Median—17 years

21.4%

17.4%

3.0%

All AH—4.34

ALH—4.76

ADH—3.93

ALH + ADH—4.36

[5]

ALH

ADH

126

150

Mean—17.5 years

12.0%

12.7%

12.0%

12.7%

 

ALH—4.2

ADH—4.3

[1]

ALH

316

Mean—17 years

ALH—12.8%

ALH + DIALH—21.3%

ALH/no DIALH-7.7%

DIALH—6.1%

ALH—12.8%

ALH + DIALH—21.3%

ALH/no DIALH-7.7%

DIALH—6.1%

 

ALH—4.3

ALH + DIALH-6.8

ALH/no DIALH-2.7 DIALH—2.1

[14]

ADH

82

Mean—12.4 years

9.8%

9.8%

  

[70]

ALH

ALH all—252

ALH alone—161

ALH + DIALH—76

ALH + ADH—15

 

ALH all—20%

ALH alone—16%

ALH + DIALH—24%

ALH + ADH—40%

ALH all—20%

ALH alone—16%

ALH + DIALH—24%

ALH + ADH—40%

 

Invasive carcinoma—3.1

[2]

To further define the genomic changes of AH, a comprehensive review of the literature was conducted to include all references describing numerical chromosomal changes, structural chromosomal changes, epigenetic changes, and changes in gene expression in atypical ductal and atypical lobular hyperplasia of the breast. The relationship of these genomic changes to those of associated synchronous breast cancer, and to the development of metachronous breast cancer, is discussed. A model summarizing the developmental pathways of AH is described.

Methods

Literature search and criteria for identification of tissue specimens

A literature search was conducted through PubMed and cross references to identify all reports of atypical ductal hyperplasia, atypical lobular hyperplasia, or simply atypical hyperplasia of the breast which described studies of molecular changes in four genomic categories: numerical chromosomal changes, structural chromosomal changes, DNA methylation, or gene expression studies (see respective Tables below for references describing methods of analyses). The criteria for diagnosis of ADH and ALH are as previously described [1, 14, 15]. Proliferative epithelium with atypia, such as that acquired through random periareolar fine needle aspirate, or through breast ductal lavage, was also included. The presence of an in situ or invasive carcinoma associated with the AH lesion (such as that removed with an initial excisional biopsy) is noted, and these are referred to as being “synchronous” to indicate they occur at the same time as the primary lesion. This is in contrast to “metachronous” carcinomas which occurred at a later date and in either the ipsilateral or contralateral breast. Molecular changes in an associated breast carcinoma, either in situ or invasive, are included when available; however molecular changes in associated benign lesions such as ductal hyperplasia without atypia, flat epithelial atypia (FEA), or lobular carcinoma in situ (LCIS) are not described, and lobular neoplasia is included only if specific molecular changes in an associated ALH are described.

Results and discussion

Numerical chromosomal changes in atypical hyperplasia

Studies examining chromosomal content by FISH, DNA content, or nuclear morphometry of ADH and ALH showed gains or losses of whole chromosomes compared to normal breast tissue, indicating aneuploidy is a prominent feature of atypical hyperplasia (Table 3). The chromosomal changes seen in atypical hyperplasias are similar to those present in breast cancer [16, 17, 18], and are consistent with the proposal that AHs are preneoplastic lesions and part of a continuum in the steps toward breast cancer [19, 20]. Mariuzzi et al. [17] examined the nuclear chromatin pattern in AH and found drastic changes in karyometric features, with these changes similar to those seen in comedo DCIS. Others have noted a high incidence of monoclonality (51.3%) in ADH [21], and an abnormal DNA content [6], consistent with neoplastic transformation. Eriksson et al. [22] considered the DNA cytometric findings in atypical hyperplasias to strongly indicate that, already at this early stage, complex nuclear alterations have occurred. Further evidence for this relationship is found in the studies of Cummings et al. [23] who examined specimens containing both AH and DCIS and found concordance in chromosome 1 aneuploidy between these lesions. They considered these findings to support the concept that benign proliferative breast disease is a biological precursor of in situ and invasive ductal carcinoma, the early histological changes possibly indicating a field effect with further genetic changes required for the development of a malignant phenotype [23].
Table 3

Numerical chromosomal abnormalities in atypical hyperplasia

Chromosome

Alteration

Normal breast

Atypical hyperplasia

DCIS

Invasive carcinoma

References

1

Chromosome copy number—FISH

Normal compliment

ALH—no gain or loss

Gain 100%

Gain 100%

[20]

1

Ploidy, FISH

Normal content

ADH—aneusomy, 100.0%

Gain, 72.7%

Loss, 9.1%

Gain, 87.5%

[71]

1

Chromosome copy number, FISH

Signal number—1.14

ADH—increased copy number, signal number 1.50

Increased, copy number, signal number 1.95

Increased copy number, signal number 1.74

[23]

16

Chromosome copy number—FISH

Borderline loss

ALH—gain, 50%

Gain, 100%

Gain, 100%

[20]

17

Chromosome copy number—FISH

Normal compliment

ALH—borderline loss, 50%

True gain, 100%

True gain, 100%

[20]

17

Ploidy, FISH

Normal content

ADH—no loss or gain

Gain, 45.5%

Loss, 45.5%

Gain, 50.0%

[71]

18

Chromosome copy number—FISH

Borderline loss

ALH—borderline loss 50%

Gain, 100%

Borderline gain, 100%

[20]

Chromosomes 8,11

FISH

 

Nipple aspirate fluid mild atypia—20% aneusomy

  

[72]

Chromosomes 1,8,11 or 17.

FISH

Disomy—100%

Nipple aspirate fluid, marked atypia—100% aneusomy

 

Nipple aspirate fluid, malignant, 100% aneusomy

[72]

Chromosomes

7-12, 17, 18, X

Chromosomal aberrations, cytologic, FISH

40% of non-proliferative lesions

ADH—100%

 

100% (includes DCIS)

[16]

Chromosomes 1, 7, 8, 16, 17, X

Chromosome copy number—FISH

 

ADH—no gains or losses

ALH, chromosome 8, 3% triploid

70% aneuploidy

100% aneuploidy

[73]

Nucleus—nuclear morphometry

Area

Non-proliferative 25.5

AH—37.4

47.9

54.9

[74]

 

Perimeter

Non-proliferative 20.6

AH—24.3

27.2

29.4

[74]

 

Maximum diameter

Non-proliferative 7.3

AH—8.52

9.6

10.3

[74]

 

Minimum diameter

Non-proliferative 5.1

AH—6.0

6.9

7.4

[74]

 

Large dark areas

Non-proliferative 0.022

AH—0.084

0.103

0.099

[74]

 

Large light areas

Non-proliferative 0.009

AH—0.038

0.049

0.075

[74]

 

Total stain

Non-proliferative 12.52

AH—12.38

23.73

19.72

[74]

DNA content

 

Normal diploid

ADH—diploid, 33%

Type III histogram, 33.3%

Aneuploid, 33.3%

ALH—diploid, 100%

  

[75]

DNA content

Nuclear DNA histogram

Diploid

ADH—Type III/IV histogram, 38.1%

ALH—diploid

  

[76]

DNA content

 

Hyperplasia without atypia-diploid

Aneuploid, 33.3%

Aneuploid, 78.2%

 

[19]

DNA content

Aneuploidy

 

AH—aneuploid, 30.8%

Aneuploid, 33.3%

Aneuploid, 88.5%

[77]

DNA ploidy

Cytometric assessment

Intraductal proliferation without atypia—euploid

ADH—43% aneuploidy

71.4%—84.4% aneuploidy

54.1%—95.6% aneuploidy

[78]

DNA aneuploidy

DNA histogram

 

AH—aneuploidy, 71%

Aneuploidy, 71%

 

[6]

DNA aneuploidy

DNA Index

Non-proliferative—25% aneuploidy

Hyperplasia with atypia—aneuploidy 32%

  

[79]

Nuclear morphometry

Nuclear area

13.13

AH—24.25

Cribriform—16.16

Comedo—40.23

41.30

[17]

Nuclear morphometry

Nuclear abnormality

0.644

AH—2.261

Cribriform—0.918

Comedo—2.710

1.265

[17]

Monoclonality

X-chromosome inactivation assay

0% monoclonal

AH—51.3% monoclonal

100% monoclonal

 

[21]

Nucleolar organizer regions

Ag-NOR—IHC

6.0

ADH—8.8

ALH—8.6

9.0

17.7

[18]

DNA quantitation

Aneuploidy

Euploid (NABT)

AEH—aneuploidy 50%

 

Aneuploidy 50%

[80]

Mitotic figures

Mitoses/HPF

3.5 (proliferative disease without atypia)

ADH—6.7

DCIS—26.5

DCIS in infiltrating carcinoma—51.3

 

[81]

Chromosomal abnormalities

Cytogenic, FISH

 

AEH—diploid with structural aberrations

  

[82]

NABT normal breast tissue adjacent to cancer, IHC immunohistochemistry, FISH fluorescent in situ hybridization, AEH atypical epithelial hyperplasia

Aneuploidy is an important indicator of chromosomal instability [24], resulting in significant deregulation of the transcriptome [25], aneuploidy-induced stresses [26], and contributing to further progression in the carcinogenic pathway. The causes of aneuploidy in AH are not clear; however, alterations in multiple genes known to contribute to aneuploidy have been observed in AH (Tables 4, 5, 6). For example, mutations in the tumor suppressor gene APC lead to chromosome mis-segregation as a result of kinetochore–microtubule disconnection during anaphase [27]; p53 mutations result in centrosome hyperamplification leading to multiple spindle poles and mis-segregation of chromosomes [28]; loss of p16 generates supernumerary centrosomes through centriole pair splitting, resulting in aneuploidy [29]; and BRCA1 inactivation leads to microtubule instability or centrosome amplification [30]. While speculative, one might suggest these findings indicate multiple potential pathways to the aneuploidy which is an important advanced genomic change for these lesions. Aneuploidy is also a prominent feature of high-risk normal breast tissue [31], indicating that these chromosomal changes may be a marker in general for high risk for breast cancer.
Table 4

Structural chromosomal abnormalities in atypical hyperplasia

Chromosome

Gene

Alteration

Normal breast

Atypical hyperplasia

DCIS

Invasive carcinoma

References

1p32

MYC1

MSI/LOH

 

8.3%

  

[33]

1q

 

CGH

 

ADH—gain 11.1%

  

[35]

1q

 

Chromosome copy number, CGH

 

ADH—gain 33.3%

Gain, 60%

Gain, 80%

[83]

1q32-42/D1S549, D1S213

 

LOH (proportion)

2%

ADH with cancer, 29%

52%

44%

[32]

1q32-42/D1S549

 

MSI/LOH

 

AH—25.0%

  

[33]

1q32-qter

 

CGH

 

ADH—high-level amplification

  

[7]

2p11.2

 

CGH

 

ALH—gains, 50%

  

[84]

2q35/D2S362

 

LOH

 

ADH non-cancerous breast—none

ADH cancerous breast—6%

Non-comedo—6%

Comedo—9%

 

[85]

3p

rhoA, cdc25A

CGH

 

ADH—gains

  

[83]

3p24/D3S1298

 

MSI/LOH

 

AH—8.3%

  

[33]

3p22ter

 

CGH

 

ADH gain, 67%

 

Gain, 60%

[83]

3q11-q21

 

CGH

 

ADH loss, 11.1%

  

[35]

5p

 

CGH

 

Gain

Gain

Gain

[7]

5p14

 

CGH

 

ADH—high-level amplification

  

[7]

5q32-33.1

CSF1R

CGH

 

ALH—gain

  

[84]

6q

 

Chromosomal imbalance, CGH

 

ALH—gain, 36%

Gain, 22%

Gain, 2%

[86]

6qter/D6S417

 

LOH

 

ADH non-cancerous breast—6%

ADH cancerous breast—9%

Non-comedo—17%

Comedo—11%

 

[85]

6g21ter

 

CGH

 

ADH—gain, 33.3%

Gain, 40%

Gain, 60%

[83]

6q27-qter

SEN6

FISH, cytogenetic

 

ADH—large deletion present

  

[87]

7p11.2-p11.1

 

CGH

 

ALH—Loss, 83.3%

  

[84]

7p12-15

EGFR

Microsatellite analysis

30.0%

ADH of cancer subject—80%

100.0%

100.0%

[88]

7p22-qter

 

CGH

 

ADH—high-level amplification

  

[7]

7q35ter

 

CGH

 

ADH—gain, 33.3%

 

Gain, 40%

[83]

8p

NRG1 (just distal to region)

CGH

 

ADH—loss

Loss

Loss

[7]

8p/D8S339

 

LOH

 

ADH with cancer—≥ 25%

 

≥35%

[34]

8p12-pter

 

CGH

 

ADH—Loss, 11.1%

  

[35]

8q

 

CGH

 

ADH—high-level amplification

  

[7]

8q21-qter

 

CGH

 

ADH—gain, 11.1%

  

[35]

8q24

MYC

  

ADH—gain, 66.0%

Gain, 60%

Gain, 80%

[83]

8q24

MTSS1; MYC

AI

0.0%

ADH—35%

29%

13%—37%

[89]

9p/D9S157

 

LOH

 

ADH non-cancerous breast—8%

Non-comedo—10%

Comedo—11%

 

[85]

9p21

 

AI

5%

ADH—8%

16%

11%–28%

[89]

10q25ter

 

CGH

 

ADH—gain, 33.3%

Gain, 40%

Gain, 80%

[83]

10q26

 

CGH

 

ADH-high-level amplification

  

[7]

11p15/D11S988

 

LOH

 

ADH non-cancerous breast—15%

ADH cancerous breast—38%

Non-comedo—18%

Comedo—19%

 

[85]

11p15

THO1

LOH (proportion)

 

ADH with cancer—8%

37%

28%

[32]

11q12-13

 

CGH

 

ADH—gain, 11.1%

  

[35]

11q13(PYGM)

PYGM

LOH

None

ADH—8.5%

27.6%

 

[90]

11q13

INT-2 or PYGM

LOH

 

ALH—10.5%

 

33.3%

[91]

11q13

 

CGH

 

ADH—gain, 33.3%

Gain, 40%

Gain, 80%

[83]

11q13.1

 

AI

0.0%

ADH—8%

9%

21%–30%

[89]

11q13/11q22-23/D11s1818, D11s1819

PYGM

LOH (proportion)

 

ADH with cancer—11%

35%

57%

[32]

11q23.3

 

AI

4%

ADH—8%

21%

25%–50%

[89]

11q24ter

 

CGH

 

ADH—gain, 33.3%

Gain, 20%

Gain, 40%

[83]

12p13-pter

 

CGH

 

ADH—high-level amplification

  

[7]

12q24

 

CGH

 

ADH—gain, 33.3%

Gain, 20%

Gain, 80%

[83]

13q11-22

 

CGH

 

ADH—loss, 66%

Loss—100%

Loss—100%

[83]

13q13/D13S137

 

LOH

 

ADH non-cancerous breast—13%

ADH cancerous breast—9%

Non-comedo—17%

Comedo—13%

 

[85]

13q32-q34

 

CGH

 

ADH—high-level amplification

  

[7]

14q11.2-q12

 

CGH

 

ADH—high-level amplification

  

[7]

14q24/D14S62

 

LOH

 

ADH non-cancerous breast—none

ADH cancerous breast—12%

Non-comedo—16%

Comedo—18%

 

[85]

14q32

 

CGH

 

ADH—gain, 33.3%

Gain, 20%

Gain, 40%

[83]

14q32.33

ATK1

CGH

 

ALH- gain

  

[84]

15q23-25

c-src -1

CGH

 

ADH—gain, 67%

  

[83]

15q25-qter

 

CGH

 

ADH—high-level amplification

  

[7]

15q26

 

CGH

 

ADH—gain, 66.0%

Gain, 40%

Gain, 100%

[83]

16p

 

Chromosome copy number, CGH

 

ALH—loss, 57% loss

Loss, 6%

Loss, 1%–13%

[86]

16p

 

Chromosome copy number/CGH

 

ADH—gain, 33.3%

Gain, 80%

Gain, 100%

[83]

16q

 

LOH

 

Atypical hyperplasia—50%

 

71.4%

[92]

16q

CDH1

LOH

Mutation

 

ALH—7.7%

ALH—frameshift mutation, 7.7%

  

[93]

16q

Matrix metalloproteinase 2, NME3

CGH

 

ADH—loss, 33.3%

  

[83]

16q

 

CGH

 

ADH—loss, 55.5%

  

[35]

16q

 

CGH

 

ALH—loss, 36%

Loss, 17%

Loss, 25%–67%

[86]

16q

CDH1, E2F4, WWOX

CGH

 

ADH—loss

Loss

Loss

[7]

16q/D16S413

 

LOH

 

Atypical ductal hyperplasia—55.6%

  

[94]

16q/D16S422

CDH13

LOH

 

ADH with cancer—≥25%

 

≥35%

[34]

16q21-q23.1

CDH1

CGH

 

ALH—loss, 25%

  

[84]

16q21-24/D16s265, D16s402, D16s413, D16s512

 

LOH (proportion)

2%

ADH—52%

63%

78%

[32]

17p

 

CGH

 

ADH—loss 22.2%

  

[35]

17p

P53

CGH

 

ADH—loss

Loss

Loss

[7]

17p13/D17S796

Close to P53

LOH

 

ADH in normal adjacent to cancer—33.3%

100%

100%

[95]

17p13/D17S960

P53 candidate gene

LOH

 

ADH non-cancerous breast—11%

ADH cancerous breast—8%

Non-comedo—31%

Comedo—37%

 

[85]

17p13.1

TP53

Microsatellite alterations

 

AH—16.6%

  

[33]

17p13.1/D17s796, D17s525

TP53

LOH (proportion)

 

ADH with cancer—6%

42%

59%

[32]

P53

TP53

Mutations

 

ADH—mutations in 50%

  

[46]

17p13.2/D17S796

Within 2 cM of p53

LOH

 

ADH—25.0%

  

[94]

17q

HER-2/neu, GRB7, TBX2, STARD3, MLN64/

CAB1, and ESTIMAGE68400

CGH

 

ADH—gain

  

[7]

17q11/NF1

 

LOH

 

ADH non-cancerous breast—14%

ADH cancerous breast—10%

Non-comedo—27%

Comedo—15%

 

[85]

17q21

 

AI

0.0%

ADH—7%

30%

19%–27%

[89]

17q21/D17S579

Region of BRCA1

MSI/LOH

 

AH—8.3%

  

[33]

D17S8000

BRCA1

LOH

 

ADH ≥25%

  

[34]

20p11.2-p13

 

CGH

 

ADH—high-level amplification

  

[7]

20q

AIB1, TFAP2C, STK15

CGH

 

ADH—gain

Gain

Gain

[7]

20q

 

Chromosomal copy number alterations/CGH

None

ADH –amplified 100%

100% show amplification

100% show amplification

[96]

20q13

 

CGH

 

ADH—gain, 100%

Gain-100%

Gain, 100%

[83]

20q13 region

 

Chromosomal copy number

None

ADH—amplified 100%

Amplified- 100%

Amplified, 100%

[96]

22q

 

CGH

 

ADH—gain 67%

Gain- 60%

Gain, 80%

[83]

22q

 

Chromosomal imbalance/CGH

 

ALH—43%

Loss, 28%

13%–20%

[86]

22q11.1

 

CGH

 

ALH—loss, 50%

  

[84]

Xp

 

CGH

 

ADH—loss

Loss

Loss

[7]

Xq

 

CGH

 

ADH—gain

Gain

Gain

[7]

AI allelic imbalance, LOH loss of heterozygosity, CGH comparative genomic hybridization

Table 5

DNA methylation of genes in atypical hyperplasia

Gene

Analysis

Gene function

Novel capability towards carcinogenesis [40, 41]

Normal breast

Atypical hyperplasia

DCIS

Invasive carcinoma

References

APC

MSP

Regulates myc and cyclin D1 expression, cell cycle entry and progression

Tissue invasion and metastases

15%

65%

72%

84%

[8]

APC

MSP

 

Tissue invasion and metastases

7%

ADH—27%

34%

38%

[43]

β-catenin (CTNNB1)

MSP

Regulates coordination of cell–cell adhesion and gene transcription

 

10%

19%

34%

44%

[8]

BRCA1

Promoter methylation

Tumor suppressor gene, DNA repair, transcriptional regulation

Limitless replicative potential

18%

22%

 

29%

[97]

CDH1

Methylation

Epithelial cell–cell adhesion, suppresses invasion and metastasis

Tissue invasion and metastases

 

ALH—100.0%

 

92.9%

[42]

CDH1

MSP

 

Tissue invasion and metastases

15%

ADH—35%

50%

65%

[8]

Cyclin D2

Methylation

Cell cycle regulation

Limitless replicative potential

Unmethylated

ADH—endoscopy, 16.7%

ADH—ductal lavage, 30.0%

28.6%

50.0%

[98]

Cyclin D2

Methylation

  

Unmethylated normal breast

ADH—endoscopy, 16.7%

33.3%

42.1%

[98]

Cyclin D2

Methylation

  

Benign ductal lavage—6.7%

Atypia—ductal lavage, 30.0%

100%

 

[98]

DLEC1

Methylation

  

7%

ADH—33%

37%

40%

[43]

ESR1

MSP

Regulation of cell proliferation

Self-sufficiency in growth signals

40%

ADH—48%

34%

51%

[8]

14-3-3σ

MSP analysis

Cell cycle regulation

Limitless replicative potential

Unmethylated

38%

83%

96%

[99]

GRIN2B

Methylation

  

0%

3%

23%

32%

[43]

GSTPI

MSP

Drug metabolism

 

5%

ADH—10%

16%

19%

[8]

HIN-1

Methylation

Tumor suppressor function, regulates cell cycle progression and apoptosis

Insensitivity to antigrowth signals

3%

ADH—23%

34%

36%

[43]

HOXA1

Methylation

Regulates gene expression, morphogenesis, differentiation

 

13%

ADH—43%

80%

76%

[43]

MINT17

Methylation Index

  

16%

24%

26%

30%

[100]

MINT31

Methylation Index

  

5%

10%

21%

13%

[100]

MTIG

MSP

  

0%

ADH—7%

14%

32%

[43]

p16INK4A

Methylation

Cell cycle regulation

Limitless replicative potential

7.5% (UDH)

35.0%

Low grade, 50%

High grade, 66%

Low grade, 71.4%

High grade, 75.0%

[101]

p16INK4A (TSG)

Methylation (MethyLight)

  

Usual ductal hyperplasia, 7.5%

35.0%

Low grade, 50.0% High grade, 68.2%

 

[102]

p16INK4A (TSG)

Percentage methylated (MethyLight)

Tumor suppressor gene

 

Normal breast/UDH, 7.5%

35.0% %

Low grade, 50.0%

High grad, 66.7% %

75.0%

[101]

p16INK4A (TSG)

IHC protein expression

  

Normal breast/UDH, 80.0%

47.5%

Low grade, 33.3% High grade, 30.6%

18.8%

[101]

RASSF1A

Methylation

Regulates cell cycle, apoptosis

Self-sufficiency in growth signals

40%

77%

89%

76%

[43]

RASSF1A

Methylation Index

  

39%

67%

79%

76%

[100]

RARβ

MSP

Cell cycle arrest, growth inhibition, apoptosis

Limitless replicative potential

7%

ADH—7%

31%

26%

[43]

RARβ

Methylation Index

 

Limitless replicative potential

16%

29%

28%

22%

[100]

RARβ

Methylation

 

Limitless replicative potential

Unmethylated

ADH—endoscopy, 33.3%

ADH—ductal lavage, 30.0%

50%

34%

[98]

RARβ

Methylated

Tumor suppressor gene

 

Normal breast tissue, unmethylated

ADH—endoscopy, 33.3%

14.3%

60.0%

[98]

RARβ

Methylation

  

Benign breast—4.4%

Atypia—ductal lavage, 30.0%

100.0%

 

[98]

SFRP1

Methylation

  

13%

3%

26%

46%

[43]

SFRP4

Methylation

  

0%

ADH—7%

6%

18%

[43]

TIMP3

MSP

Inhibit metalloproteinases, tissue remodeling and tumor cell progression

Tissue invasion and metastases

45%

ADH—62%

44%

56%

[8]

TMEFF2

Methylation

  

40%

ADH—47%

86%

76%

[43]

Twist

Methylation

Modulates p53

Evading apoptosis

 

ADH endoscopy—20% methylated

ADH—ductal lavage, unmethylated

28.6%

42%

[98]

MSP methylation-specific PCR; values area percent methylated

Table 6

Gene expression abnormalities in atypical hyperplasia

Gene

Alteration/analysis

Function

Normal breast

Atypical hyperplasia

DCIS

Invasive carcinoma

References

Cox-2

IHC

  

ALH—61.4%

ADH—23.0%

ADH + ALH—53.9%

  

[103]

Cyclin A

ISH

Cell cycle regulation, binds and activates CDK2 and CDK1 kinases, and promotes both cell cycle G1/S and G2/M transitions

Benign breast tissue—35.3%

ADH—62.5%

42.1–46.4%

77.8%

[104]

Cyclin D1

IHC

 

Normal breast—11.7%

PDWA—25.0%

ADH—39.4%

43.6–47.9%

48.3%

[105]

Cyclin D1

Gene amplification

 

Normal breast—15%

27%

35%

25%

[106]

Cyclin D1

IHC

 

Normal breast—13%

57%

50%

64%

[106]

Cyclin D2

Methylation

A regulatory subunit of CDK4 or CDK6, whose activity is required for cell cycle G1/S transition; involved in the phosphorylation of tumor suppressor protein Rb

Unmethylated normal breast tissue

ADH—endoscopy, 16.7% methylated

33.3%

42.1%

[98]

Cyclin D2

Methylation

 

Benign ductal lavage—6.7%

Atypia—ductal lavage, 30.0% methylated

100.0%

 

[98]

EGFR (HER-1)

IHC

Regulate cell growth, differentiation, and survival

Non-proliferative—21%

Epithelial hyperplasia with atypia—60%

  

[79]

EZH2

IHC

Transcriptional repression

Normal breast—0.0%

ADH without DCIS—10%

ADH with DCIS—40.0%

45%

 

[52]

FHIT

IHC/H-score

Controls proliferation and apoptosis

Normal adjacent to cancer, strong and uniform, 100%; 2.95/3.0

Loss of FHIT protein vs normal

Marked loss of FHIT protein, 75%

Marked loss of FHIT protein, 54%; 0–1.0/3.0

[107]

FHIT

mRNA

 

Normal adjacent to ADH, 86%

71%

45%

29%

[108]

FHIT

Western blot

 

82%

Normal adjacent to AH

57%

45%

27%

[108]

HER-2/neu

Amplification FISH

 

Normal adjacent to ADH, no amplification

ADH—53.8% amplified

95.5% amplified

100% amplified

[109]

HER-2/neu (C-erbB-2)

IHC

 

Non-proliferative—15%

Epithelial hyperplasia with atypia—40%

  

[79]

HER-2/neu (C-erbB-2)

IHC

 

Ductal hyperplasia without atypia—13.3%

Atypia (mild—severe), 30–56.6%

31.9%

17.8%

[110]

Myc

IHC

 

Benign lesions, 31%

66.7%

45%

66.7%

[111]

P53

Sequencing, mutations

  

ADH—28.6%, insertion, deletion

 

34.1%

[45]

P53

Mutation-gel elect

  

ADH—1 case

31.5%

55.7%

[47]

P53

SSCP, sequencing; mutation

 

Normal adjacent to cancer, no mutations

ADH—50% (not adjacent to cancer)

50%

 

[46]

RB

IHC

 

Normal breast, weak staining

ADH, mod/strong—11%

Mod/strong—64%

Mod/strong—47%

[112]

Stat3

IHC

Regulates genes that are involved in cell growth and division, cell movement, and apoptosis

Normal breast, 12.8%

ADH, 30.0%

ADH adjacent to breast cancer, 31.15%

  

[113]

Stat5

IHC

 

Normal breast, 17.1%

ADH—31.65%

  

[113]

Telomere, anaphase bridges

FISH

  

ADH—16.7%

18.2%

 

[114]

Telomerase activity

TRAP signal

 

Benign breast disease, 14.0%

Atypical hyperplasia, 100%, focal high expression

92% strong

94% strong

[115]

Telomerase

Human telomerase gene (hTR)

 

Simple hyperplasia, 16.6%

ADH mild—22%

ADH moderate—33.3%

ADH severe—60.9%

85.7%

91.7%

[116]

Telomerase

Human reverse transcriptase gene (hTRT)

 

Simple hyperplasia, 0.0%

ADH mild—11.1%

ADH moderate—25.0%

ADH severe—52.1%

78.6%

83.3%

[116]

α-tubulin

mRNA expression-percent positive

Structural components of centrosomes

Normal breast, 33.3%

ADH—62.5%

82.5%

77.5%

[49]

α-tubulin

Protein expression

 

Normal breast, 31.7%

ADH—65%

86.3%

87.5%

[49]

α-tubulin

DNA copy number

 

Normal breast, 2.05

ADH—4.31

5.54

5.15

[49]

 

Centrosome abnormality-frequency

 

Normal breast, 0%

ADH—30%

52.5%

70.0%

[49]

γ-tubulin

mRNA expression-percent positive

 

Normal breast, 30.0%

ADH 57.5%

85.0%

82.5%

[49]

γ-tubulin

Protein expression

 

Normal breast 35.0%

ADH—58.8%

86.3%

85.0%

[49]

Ki67

IHC

 

Normal breast, 1.5%

PBBD without atypia, 3.5%

PBBD with atypia, 16%

Non-high-grade, 6.1%

High grade, 17.3%

 

[54]

Ki67

IHC

 

Normal breast, 0.1%

Usual hyperplasia, 3.3%

ADH—8.2%

8.7%

21.1%

[117]

PDWA proliferative benign breast disease without atypia, IHC immunohistochemistry, ISH In situ hybridization, PBBD Proliferative benign breast disease

Structural chromosomal changes in atypical hyperplasia

The genomic progression from normal breast tissue to atypical hyperplasia is accompanied by the development of multiple structural chromosomal abnormalities in the form of loss of heterozygosity [(LOH)/allelic imbalance (AI)] identified by microsatellite markers, and the development of large-scale chromosomal gains and losses identified by comparative genomic hybridization (CGH). These are summarized in Table 4, and it can be seen that these alterations involve multiple chromosomes and a wide range of chromosomal loci. The LOH/AI changes in AH have been shown to involve all informative markers on a chromosome arm, consistent with the pattern found in breast cancer, and in contrast to normal breast tissue and ductal hyperplasia where AI involved only single markers [32]. Atypical hyperplasia lesions are considered to be monoclonal microsatellite alterations involving both length variation and allele loss [33], and which may involve multiple genes such as Myc, EGFR, CDH13, BRCA1, p53 (Table 4). Amari et al. [34] studied 23 synchronous lesions of ADH, DCIS, and invasive carcinoma. ADH tumors with LOH were always accompanied by LOH in DCIS and IDC, consistent with ADH having a high risk of developing malignant transformation. LOH/AI is an important mechanism for loss of tumor suppressor and other genes and would contribute to the development and progression of AH.

AH has been studied by comparative genomic hybridization (CGH) to identify larger-scale structural chromosomal abnormalities. The majority of these studies utilized metaphase spreads with a resolution of ≥10 Mb. These studies identified multiple deletions and amplifications both within and between chromosomes of AH (Table 4). Chromosomes 1q, 6q, 8q, 11q, 14q were among the most frequently involved and often exhibited chromosomal gains. Gao et al. [7] reported high-level amplifications at multiple chromosomal sites, and many of these were gains, including those at 1q, 5p, 8q, 12q, 20q, and Xq, which were shared by ADH, DCIS, and invasive carcinoma. Gong et al. [35] on the other hand found five of the nine ADH lesions showing chromosome copy number alterations, with 16q loss and 17p loss being the most frequent changes. Candidate genes that might be associated with some of these losses included E-cadherin on 16q and p53 on 17p. The loss of material from chromosomes 16 and 17 was also consistent with the LOH analyses of AH (Table 4). Together, the presence of large-scale amplifications and deletions is consistent with gross chromosomal rearrangements in atypical hyperplasias. These genomically advanced changes also occur with the transition of normal adjacent breast tissue (a high-risk tissue) to breast cancer, and with the progression of HMEC’s to telomere-based crises, and are considered to be the types of chromosomal abnormalities seen in the earliest lesions of breast cancer [31, 36]. It is also noteworthy that DNA double-strand breaks (DSB) are considered to be an important etiologic mechanism in the development of both LOH [37] and GCR [38]. DSBs are an important consequence of estrogen exposure, and the average age of women with AH is over 55 years of age [4, 39], representing forty or more years (from menarche) of estrogen exposure, with the potential to induce these changes.

DNA methylation of genes in atypical hyperplasia

DNA methylation of CpG islands in the promoter region of a gene is an important mechanism for the silencing of tumor suppressor and other genes. Studies of atypical hyperplasia have identified multiple genes which may be methylated in these lesions, including tumor suppressor genes known to be important in breast carcinogenesis (Table 5; APC, BRCA1, CDH1, 14-3-3σ, HIN-1, P16, RASSF1A, RARβ). A number of cellular processes may be altered by inactivation of these genes, including cell cycle control, DNA repair, cell–cell adhesion, cell proliferation, apoptosis, cellular differentiation, and centrosome and mitotic events. Importantly, methylation in AH involves genes which are also instrumental in five of the six capabilities a cell has to acquire to become malignant (tissue invasion and metastases, limitless replicative potential, self-sufficiency in growth signals, insensitivity to antigrowth signals, and evading apoptosis) [40, 41], supporting an early and important role in breast carcinogenesis. A review of Table 5 indicates there is clearly heterogeneity in the incidence of methylation in these lesions, and in some cases methylation may also be monoallelic (CDH1) [42], further contributing to a range of gene inactivation. DNA methylation of tumor suppressor and other genes appears to play an important role in the progression of AH to breast cancer. Park et al. [43] examined methylation patterns in synchronous ADH, DCIS, and invasive ductal carcinoma. They found overall methylation levels and frequencies of APC, DLEC1, HOXA1, and RASSF1A promoter CpG islands were significantly higher in ADH than in normal breast tissue, while GRIN2B, GSTP1, HOXA1, RARβ, RUNX3, SFRP1, and TMEFF2 showed higher methylation levels and frequencies in DCIS than in ADH. This indicated that promoter methylation changed significantly in pre-invasive lesions and suggested that CpG island methylation of tumor-related genes is an early event in breast cancer progression. Hoque et al. [8] studied synchronous ADH, DCIS, and invasive ductal carcinoma. For the genes APC, CDH1, and CTNNB1 they found methylation at two or three gene loci in 25% of ADH, 28% of DCIS, and 37% in IDC. They noted atypical ductal hyperplasia and in situ carcinoma showed similar methylation patterns, suggesting that atypical hyperplasia should be considered as a well-differentiated or simply small in situ carcinoma. DNA methylation may also contribute to chromosomal abnormalities in AH. It was seen above that APC and p16INK4a regulate centrosome duplication and chromosome segregation, and loss of these genes through DNA methylation would be expected to contribute to chromosomal instability and aneuploidy [27, 29]. Together these findings indicate that DNA methylation is not only involved in the formation of AH and contributes significantly to its genomic instability, but also plays an important role in subsequent progression to malignancy.

Gene expression abnormalities

The development of ADH and progression to DCIS and invasive breast cancer is accompanied by the acquisition of multiple gene expression differences. This is demonstrated both by gene expression profiling studies and by multiple individual gene expression studies. Ma et al. [9] examined gene expression profiling in specimens containing invasive ductal carcinoma (IDC)/DCIS/ADH/adjacent normal tissue. They found that, as compared with the patient-matched adjacent normal epithelium, significant global alterations in gene expression occurred in ADH, and these alterations were maintained in the later stages of DCIS and IDC. All of the ADH samples demonstrated a grade I gene expression signature and clustered with the low-grade DCIS and IDC samples. These three distinct stages of breast cancer (ADH, DCIS, IDC) were thus highly similar to each other at the level of the transcriptome, supporting the idea that the distinct stages of progression are evolutionary products of the same clonal origin [9].

Studies of individual genes in atypical hyperplasia indicate altered expression in multiple genes effecting a wide range of signaling pathways and cellular functions (Table 6), further supporting the gene expression profiling differences between ADH and normal adjacent tissue described above. These genes include estrogen receptor and estrogen-related genes (ER, EZH2), cell cycle genes (cyclin A1, D1, D2), loss of tumor suppressor genes (FHIT, p16, p53, RARβ) increased mitogenic activity of growth factors and oncogenes (EGFR, Her-2/neu, myc), and increased expression of transcription factors (STAT 3,5). Together these alterations may contribute to increased estrogen responsiveness, increased cell cycle progression, development of aneuploidy, decreased apoptosis, and loss of cell–cell adhesion. Alterations in many of these genes may also be associated with increased proliferation which is confirmed by increased expression of Ki67 (Table 6), a measure of cellular proliferation. Interestingly, Ki67 has also been found to be a time-varying biomarker of risk of breast cancer in women with atypical hyperplasia [44]. There is evidence that p53 is mutated in ADH [45, 46, 47]. The presence of a dysfunctional p53 could have widespread effects in these cells including loss of cell cycle arrest and apoptosis, altered DNA repair, and genomic instability [48]. Alterations in α-tubulin and γ-tubulin are also observed in AH [49], further disrupting chromosome segregation and contributing to the aneuploidy which is observed in atypical hyperplasia (see above, numerical chromosomal changes). Importantly, it can be seen in Table 6 that for virtually all of these genes (a) the expression in ADH is altered compared with that of normal and/or non-proliferative breast tissue, and (b) this expression difference is maintained or increased in DCIS and invasive breast cancer. This is further evidence that multiple genes regulating multiple cellular processes contribute to formation of ADH and its genomic instability and are instrumental in the progression of ADH to DCIS and invasive breast cancer.

Estrogen receptor in atypical hyperplasia

The expression of ERα in atypical hyperplasia is high [12, 50], and in some series all of the ADH lesion expressed ER [12, 51], consistent with both a prominent sensitivity to estrogens and a clonally expanded population of cells. Estradiol is an important mitogen, and the increased ER content promotes proliferation and clonal expansion, while at the same time increasing the accumulation of mutational changes. The gene EZH2 is also increased in AH and DCIS [52], and this gene transactivates genes that are commonly targeted by estrogen and WNT signaling pathways and promotes cell cycle progression in breast cancer cells [53]. The functional ER and its role in proliferation also makes it an excellent potential target for antiestrogen prevention therapy. Efficacy of tamoxifen in the prevention of breast cancer in women with AH was demonstrated in the NSABP-P1 trial [13]. Closely related to this point, the finding that antiestrogen therapy reduces breast cancer development in the ipsilateral and contralateral breast indicates that this characteristic of AH (ER positivity) is reflected in the genomic characteristics of the remaining normal breast tissue. If other genomic characteristics of AH are also reflected in these normal tissues, then the molecular profile of AH could be important for assessing future risk and responsiveness of these normal tissues. Lastly, the expression of ERβ is decreased in atypical hyperplasia [54]. ERβ is considered to play an oncosuppressive role in breast cancer [55]. Low ERβ2 expression, combined with increased ERα expression could further promote progression along the AH-DCIS/invasive carcinoma pathway.

Metachronous breast cancer associated with atypical hyperplasia

Women with AH are at significant risk for the development of metachronous breast cancer (MBC), and it is noteworthy that the characteristics of this event for AH are very similar to those of women with sporadic breast cancer for the development of contralateral breast cancer (CBC): (a) AH contains multiple advanced genomic changes including aneuploidy, gross chromosomal rearrangements, and DNA methylation of tumor suppressor genes, all of which are common in sporadic breast cancer. (b) Both MBC and CBC are more commonly invasive breast cancer, less commonly DCIS (Table 2) [56]. (c) The cumulative incidence of breast cancer appears to increase linearly over time in both MBC [5] and CBC [56, 57]. (d) The annual incidence of breast cancer development of MBC (estimated to be approx. 0.9%/year from Hartmann [5], Fig. 2) is very similar to 0.6–0.7%/year for CBC [56, 58]. (e) The incidence of both MBC and CBC are reduced by antiestrogens [13, 59]. Together, these findings indicate that many of the features of carcinogenesis of AH are shared by sporadic breast cancer, and have strong carcinogenic potential for the future development of metachronous breast cancer.

Summary and conclusions

Atypical ductal and atypical lobular hyperplasia possess a wide range of advanced genomic changes including aneuploidy, loss of heterozygosity, gross chromosomal rearrangement such as amplifications and large-scale deletions, DNA methylation of tumor suppressor and other genes, and gene expression differences which are associated with a significant risk for breast cancer. These genomic changes progress from associated normal breast tissue, indicating an important role in the development of ADH. Many of these genomic charges are also shared by synchronously associated DCIS and invasive carcinoma, suggesting they are an important part of the progression of atypical hyperplasia to breast cancer. At the same time many of these changes, including ER expression, are also shared by standard sporadic breast cancer and thus reflect the propensity of distant normal breast tissue to develop metachronous or contralateral breast cancer. These developmental patterns and relationship of AH to breast cancer are summarized in Fig. 1. Knowledge of a comprehensive profile of the genomic changes of AH should increase our understanding of high-risk lesions of the breast, promote identification of new targets for breast cancer prevention, and clarify progression in the carcinogenic pathway.
Fig. 1

Development and progression of atypical hyperplasia to breast cancer. Atypical hyperplasia (ALH or ADH) develops within a cancerized field in normal breast tissue (Fig. 1) [31, 118]. AH may present as a solitary lesion (single or multifocal). Local progression of AH results in the development of DCIS/IDC which appear synchronously with the AH. Excision of the primary AH (solitary or with synchronous carcinoma) may then be followed by the development of metachronous breast cancer—DCIS/IDC/ILC. Included in Fig. 1 is a separate pathway in which breast cancer develops without any intervening atypical lesion

Notes

Funding

This research was supported by the Intramural Research Program, National Cancer Institute, Center for Cancer Research, National Institutes of Health, Bethesda, MD.

Compliance with ethical standards

Conflict of interest

The author is employed by the National Institutes of Health which funded this manuscript. The author has no conflicts of interest with the NIH.

References

  1. 1.
    Page DL, Dupont WD, Rogers LW, Rados MS (1985) Atypical hyperplastic lesions of the female breast. A long-term follow-up study. Cancer 55(11):2698–2708PubMedGoogle Scholar
  2. 2.
    Page DL, Schuyler PA, Dupont WD, Jensen RA, Plummer WD Jr, Simpson JF (2003) Atypical lobular hyperplasia as a unilateral predictor of breast cancer risk: a retrospective cohort study. Lancet 361(9352):125–129PubMedCrossRefGoogle Scholar
  3. 3.
    Roy D, Liehr JG (1999) Estrogen. DNA damage and mutations. Mutat Res 424(1–2):107–115PubMedGoogle Scholar
  4. 4.
    Degnim AC, Visscher DW, Berman HK, Frost MH, Sellers TA, Vierkant RA, Maloney SD, Pankratz VS, de Groen PC, Lingle WL, Ghosh K, Penheiter L, Tlsty T, Melton LJ III, Reynolds CA, Hartmann LC (2007) Stratification of breast cancer risk in women with atypia: a Mayo cohort study. J Clin Oncol 25(19):2671–2677PubMedCrossRefGoogle Scholar
  5. 5.
    Hartmann LC, Degnim AC, Santen RJ, Dupont WD, Ghosh K (2015) Atypical hyperplasia of the breast–risk assessment and management options. N Engl J Med 372(1):78–89PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Crissman JD, Visscher DW, Kubus J (1990) Image cytophotometric DNA analysis of atypical hyperplasias and intraductal carcinomas of the breast. Arch Pathol Lab Med 114(12):1249–1253PubMedGoogle Scholar
  7. 7.
    Gao Y, Niu Y, Wang X, Wei L, Lu S (2009) Genetic changes at specific stages of breast cancer progression detected by comparative genomic hybridization. J Mol Med 87(2):145–152PubMedCrossRefGoogle Scholar
  8. 8.
    Hoque MO, Prencipe M, Poeta ML, Barbano R, Valori VM, Copetti M, Gallo AP, Brait M, Maiello E, Apicella A, Rossiello R, Zito F, Stefania T, Paradiso A, Carella M, Dallapiccola B, Murgo R, Carosi I, Bisceglia M, Fazio VM, Sidransky D, Parrella P (2009) Changes in CpG islands promoter methylation patterns during ductal breast carcinoma progression. Cancer Epidemiol Biomarkers Prev 18(10):2694–2700PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Ma XJ, Salunga R, Tuggle JT, Gaudet J, Enright E, McQuary P, Payette T, Pistone M, Stecker K, Zhang BM, Zhou YX, Varnholt H, Smith B, Gadd M, Chatfield E, Kessler J, Baer TM, Erlander MG, Sgroi DC (2003) Gene expression profiles of human breast cancer progression. Proc Natl Acad Sci USA 100(10):5974–5979PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Murray MP, Luedtke C, Liberman L, Nehhozina T, Akram M, Brogi E (2013) Classic lobular carcinoma in situ and atypical lobular hyperplasia at percutaneous breast core biopsy: outcomes of prospective excision. Cancer 119(5):1073–1079. doi: 10.1002/cncr.27841 PubMedCrossRefGoogle Scholar
  11. 11.
    Shah-Khan MG, Geiger XJ, Reynolds C, Jakub JW, Deperi ER, Glazebrook KN (2012) Long-term follow-up of lobular neoplasia (atypical lobular hyperplasia/lobular carcinoma in situ) diagnosed on core needle biopsy. Ann Surg Oncol 19(10):3131–3138. doi: 10.1245/s10434-012-2534-9 PubMedCrossRefGoogle Scholar
  12. 12.
    Shoker BS, Jarvis C, Sibson DR, Walker C, Sloane JP (1999) Oestrogen receptor expression in the normal and pre-cancerous breast. J Pathol 188(3):237–244PubMedCrossRefGoogle Scholar
  13. 13.
    Fisher B, Costantino JP, Wickerham DL, Cecchini RS, Cronin WM, Robidoux A, Bevers TB, Kavanah MT, Atkins JN, Margolese RG, Runowicz CD, James JM, Ford LG, Wolmark N (2005) Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst 97(22):1652–1662. doi: 10.1093/jnci/dji372 PubMedCrossRefGoogle Scholar
  14. 14.
    Page DL, Dupont WD, Rogers LW (1988) Ductal involvement by cells of atypical lobular hyperplasia in the breast: a long-term follow-up study of cancer risk. Hum Pathol 19(2):201–207PubMedCrossRefGoogle Scholar
  15. 15.
    Schnitt SJ, Connolly JL, Tavassoli FA, Fechner RE, Kempson RL, Gelman R, Page DL (1992) Interobserver reproducibility in the diagnosis of ductal proliferative breast lesions using standardized criteria. Am J Surg Pathol 16(12):1133–1143PubMedCrossRefGoogle Scholar
  16. 16.
    Sneige N, Sahin A, Dinh M, El Naggar A (1996) Interphase cytogenetics in mammographically detected breast lesions. Hum Pathol 27(4):330–335PubMedCrossRefGoogle Scholar
  17. 17.
    Mariuzzi L, Mombello A, Granchelli G, Rucco V, Tarocco E, Frank D, Davis J, Thompson D, Bartels H, Mariuzzi GM, Bartels PH (2002) Quantitative study of breast cancer progression: different pathways for various in situ cancers. Mod Pathol 15(1):18–25PubMedCrossRefGoogle Scholar
  18. 18.
    Di Stefano D, Scucchi L, Limiti MR, Mingazzini PL, Marinozzi V (1996) Modifications of interphasic NORs as a diagnostic parameter of atypical lesions of the female breast. Anticancer Res 16(4A):1953–1961PubMedGoogle Scholar
  19. 19.
    Schmitt FC, Leal C, Lopes C (1995) p53 protein expression and nuclear DNA content in breast intraductal proliferations. J Pathol 176(3):233–241PubMedCrossRefGoogle Scholar
  20. 20.
    Micale MA, Visscher DW, Gulino SE, Wolman SR (1994) Chromosomal aneuploidy in proliferative breast disease. Hum Pathol 25(1):29–35PubMedCrossRefGoogle Scholar
  21. 21.
    Yu Q, Niu Y, Yu Y, Ding X, Shi Y (2009) Analysis of the progression of intraductal proliferative lesions in the breast by PCR-based clonal assay. Breast Cancer Res Treat 114(3):433–440PubMedCrossRefGoogle Scholar
  22. 22.
    Eriksson E, Schimmelpenning H, Silfversward C, Auer G (1992) Immunoreactivity with monoclonal antibody A-80 and nuclear DNA content in benign and malignant human breast disease. Hum Pathol 23:1366–1372PubMedCrossRefGoogle Scholar
  23. 23.
    Cummings MC, Aubele M, Mattis A, Purdie D, Hutzler P, Hofler H, Werner M (2000) Increasing chromosome 1 copy number parallels histological progression in breast carcinogenesis. Br J Cancer 82(6):1204–1210PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Rajagopalan H, Lengauer C (2004) Aneuploidy and cancer. Nature 432(7015):338–341PubMedCrossRefGoogle Scholar
  25. 25.
    Ried T, Hu Y, Difilippantonio MJ, Ghadimi BM, Grade M, Camps J (2012) The consequences of chromosomal aneuploidy on the transcriptome of cancer cells. Biochim Biophys Acta 1819(7):784–793PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Pfau SJ, Amon A (2012) Chromosomal instability and aneuploidy in cancer: from yeast to man. EMBO Rep 13(6):515–527PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Fodde R, Kuipers J, Rosenberg C, Smits R, Kielman M, Gaspar C, van Es JH, Breukel C, Wiegant J, Giles RH, Clevers H (2001) Mutations in the APC tumour suppressor gene cause chromosomal instability. Nat Cell Biol 3(4):433–438. doi: 10.1038/35070129 PubMedCrossRefGoogle Scholar
  28. 28.
    Liu G, Parant JM, Lang G, Chau P, Chavez-Reyes A, El-Naggar AK, Multani A, Chang S, Lozano G (2004) Chromosome stability, in the absence of apoptosis, is critical for suppression of tumorigenesis in Trp53 mutant mice. Nat Genet 36(1):63–68PubMedCrossRefGoogle Scholar
  29. 29.
    McDermott KM, Zhang J, Holst CR, Kozakiewicz BK, Singla V, Tlsty TD (2006) p16(INK4a) prevents centrosome dysfunction and genomic instability in primary cells. PLoS Biol 4(3):e51PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Kops GJ, Weaver BA, Cleveland DW (2005) On the road to cancer: aneuploidy and the mitotic checkpoint. Nat Rev Cancer 5(10):773–785PubMedCrossRefGoogle Scholar
  31. 31.
    Danforth DN Jr (2016) Genomic changes in normal breast tissue in women at normal risk or at high risk for breast cancer. Breast Cancer 10:109–146. doi: 10.4137/bcbcr.s39384 PubMedPubMedCentralGoogle Scholar
  32. 32.
    Larson PS, de las MA, Cerda SR, Bennett SR, Cupples LA, Rosenberg CL (2006) Quantitative analysis of allele imbalance supports atypical ductal hyperplasia lesions as direct breast cancer precursors. J Pathol 209(3):307–316PubMedCrossRefGoogle Scholar
  33. 33.
    Rosenberg CL, de las MA, Huang K, Cupples LA, Faller DV, Larson PS (1996) Detection of monoclonal microsatellite alterations in atypical breast hyperplasia. J Clin Invest 98(5):1095–1100PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Amari M, Suzuki A, Moriya T, Yoshinaga K, Amano G, Sasano H, Ohuchi N, Satomi S, Horii A (1999) LOH analyses of premalignant and malignant lesions of human breast: frequent LOH in 8p, 16q, and 17q in atypical ductal hyperplasia. Oncol Rep 6(6):1277–1280PubMedGoogle Scholar
  35. 35.
    Gong G, DeVries S, Chew KL, Cha I, Ljung BM, Waldman FM (2001) Genetic changes in paired atypical and usual ductal hyperplasia of the breast by comparative genomic hybridization. Clin Cancer Res 7(8):2410–2414PubMedGoogle Scholar
  36. 36.
    Romanov SR, Kozakiewicz BK, Holst CR, Stampfer MR, Haupt LM, Tlsty TD (2001) Normal human mammary epithelial cells spontaneously escape senescence and acquire genomic changes. Nature 409(6820):633–637PubMedCrossRefGoogle Scholar
  37. 37.
    Thiagalingam S, Laken S, Willson JK, Markowitz SD, Kinzler KW, Vogelstein B, Lengauer C (2001) Mechanisms underlying losses of heterozygosity in human colorectal cancers. Proc Natl Acad Sci USA 98(5):2698–2702PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Kurahashi H, Bolor H, Kato T, Kogo H, Tsutsumi M, Inagaki H, Ohye T (2009) Recent advance in our understanding of the molecular nature of chromosomal abnormalities. J Hum Genet 54(5):253–260. doi: 10.1038/jhg.2009.35 PubMedCrossRefGoogle Scholar
  39. 39.
    Hartmann LC, Schaid DJ, Woods JE, Crotty TP, Myers JL, Arnold PG, Petty PM, Sellers TA, Johnson JL, McDonnell SK, Frost MH, Jenkins RB (1999) Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer. N Engl J Med 340(2):77–84PubMedCrossRefGoogle Scholar
  40. 40.
    Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100(1):57–70PubMedCrossRefGoogle Scholar
  41. 41.
    Widschwendter M, Jones PA (2002) DNA methylation and breast carcinogenesis. Oncogene 21(35):5462–5482PubMedCrossRefGoogle Scholar
  42. 42.
    Zou D, Yoon HS, Perez D, Weeks RJ, Guilford P, Humar B (2009) Epigenetic silencing in non-neoplastic epithelia identifies E-cadherin (CDH1) as a target for chemoprevention of lobular neoplasia. J Pathol 218:265–272PubMedCrossRefGoogle Scholar
  43. 43.
    Park SY, Kwon HJ, Lee HE, Ryu HS, Kim SW, Kim JH, Kim IA, Jung N, Cho NY, Kang GH (2011) Promoter CpG island hypermethylation during breast cancer progression. Virchows Arch 458(1):73–84PubMedCrossRefGoogle Scholar
  44. 44.
    Santisteban M, Reynolds C, Barr Fritcher EG, Frost MH, Vierkant RA, Anderson SS, Degnim AC, Visscher DW, Pankratz VS, Hartmann LC (2010) Ki67: a time-varying biomarker of risk of breast cancer in atypical hyperplasia. Breast Cancer Res Treat 121(2):431–437PubMedCrossRefGoogle Scholar
  45. 45.
    Kang JH, Kim SJ, Noh DY, Choe KJ, Lee ES, Kang HS (2001) The timing and characterization of p53 mutations in progression from atypical ductal hyperplasia to invasive lesions in the breast cancer. J Mol Med (Berlin, Germany) 79(11):648–655. doi: 10.1007/s001090100269 CrossRefGoogle Scholar
  46. 46.
    Keohavong P, Gao WM, Mady HH, Kanbour-Shakir A, Melhem MF (2004) Analysis of p53 mutations in cells taken from paraffin-embedded tissue sections of ductal carcinoma in situ and atypical ductal hyperplasia of the breast. Cancer Lett 212(1):121–130PubMedCrossRefGoogle Scholar
  47. 47.
    Lisboa BW, Vogtlander S, Gilster T, Riethdorf L, Milde-Langosch K, Loning T (1997) Molecular and immunohistochemical analysis of p53 mutations in scrapings and tissue from preinvasive and invasive breast cancer. Virchows Arch 431(6):375–381PubMedCrossRefGoogle Scholar
  48. 48.
    Vousden KH, Lane DP (2007) p53 in health and disease. Nat Rev Mol Cell Biol 8(4):275–283PubMedCrossRefGoogle Scholar
  49. 49.
    Niu Y, Liu T, Tse GM, Sun B, Niu R, Li HM, Wang H, Yang Y, Ye X, Wang Y, Yu Q, Zhang F (2009) Increased expression of centrosomal alpha, gamma-tubulin in atypical ductal hyperplasia and carcinoma of the breast. Cancer Sci 100(4):580–587PubMedCrossRefGoogle Scholar
  50. 50.
    Mao XY, Fan CF, Zheng HC, Wei J, Yao F, Jin F (2010) p53 nuclear accumulation and ERalpha expression in ductal hyperplasia of breast in a cohort of 215 Chinese women. J Exp Clin Cancer Res 29(1):112PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Barnes R, Masood S (1990) Potential value of hormone receptor assay in carcinoma in situ of breast. Am J Clin Pathol 94(5):533–537PubMedCrossRefGoogle Scholar
  52. 52.
    Ding L, Erdmann C, Chinnaiyan AM, Merajver SD, Kleer CG (2006) Identification of EZH2 as a molecular marker for a precancerous state in morphologically normal breast tissues. Cancer Res 66(8):4095–4099PubMedCrossRefGoogle Scholar
  53. 53.
    Shi B, Liang J, Yang X, Wang Y, Zhao Y, Wu H, Sun L, Zhang Y, Chen Y, Li R, Zhang Y, Hong M, Shang Y (2007) Integration of estrogen and Wnt signaling circuits by the polycomb group protein EZH2 in breast cancer cells. Mol Cell Biol 27(14):5105–5119PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Roger P, Sahla ME, Makela S, Gustafsson JA, Baldet P, Rochefort H (2001) Decreased expression of estrogen receptor beta protein in proliferative preinvasive mammary tumors. Cancer Res 61(6):2537–2541PubMedGoogle Scholar
  55. 55.
    Chantzi NI, Palaiologou M, Stylianidou A, Goutas N, Vassilaros S, Kourea HP, Dhimolea E, Mitsiou DJ, Tiniakos DG, Alexis MN (2014) Estrogen receptor beta2 is inversely correlated with Ki-67 in hyperplastic and noninvasive neoplastic breast lesions. J Cancer Res Clin Oncol 140(6):1057–1066PubMedCrossRefGoogle Scholar
  56. 56.
    Gao X, Fisher SG, Emami B (2003) Risk of second primary cancer in the contralateral breast in women treated for early-stage breast cancer: a population-based study. Int J Radiat Oncol Biol Phys 56(4):1038–1045PubMedCrossRefGoogle Scholar
  57. 57.
    Robbins GF, Berg JW (1964) Bilateral primary breast cancer: a prospective clincopathological study. Cancer 17:1501–1527PubMedCrossRefGoogle Scholar
  58. 58.
    Samant RS, Olivotto IA, Jackson JS, Mates D (2001) Diagnosis of metachronous contralateral breast cancer. Breast J 7(6):405–410PubMedCrossRefGoogle Scholar
  59. 59.
    Dowsett M, Cuzick J, Ingle J, Coates A, Forbes J, Bliss J, Buyse M, Baum M, Buzdar A, Colleoni M, Coombes C, Snowdon C, Gnant M, Jakesz R, Kaufmann M, Boccardo F, Godwin J, Davies C, Peto R (2010) Meta-analysis of breast cancer outcomes in adjuvant trials of aromatase inhibitors versus tamoxifen. J Clin Oncol 28(3):509–518. doi: 10.1200/jco.2009.23.1274 PubMedCrossRefGoogle Scholar
  60. 60.
    Adrales G, Turk P, Wallace T, Bird R, Norton HJ, Greene F (2000) Is surgical excision necessary for atypical ductal hyperplasia of the breast diagnosed by Mammotome? Am J Surg 180(4):313–315PubMedCrossRefGoogle Scholar
  61. 61.
    Cohen MA (2004) Cancer upgrades at excisional biopsy after diagnosis of atypical lobular hyperplasia or lobular carcinoma in situ at core-needle biopsy: some reasons why. Radiology 231(3):617–621. doi: 10.1148/radiol.2313040154 PubMedCrossRefGoogle Scholar
  62. 62.
    Jackman RJ, Birdwell RL, Ikeda DM (2002) Atypical ductal hyperplasia: can some lesions be defined as probably benign after stereotactic 11-gauge vacuum-assisted biopsy, eliminating the recommendation for surgical excision? Radiology 224(2):548–554. doi: 10.1148/radiol.2242011528 PubMedCrossRefGoogle Scholar
  63. 63.
    Lourenco AP, Mainiero MB, Lazarus E, Giri D, Schepps B (2007) Stereotactic breast biopsy: comparison of histologic underestimation rates with 11- and 9-gauge vacuum-assisted breast biopsy. Am J Roentgenol 189(5):W275–W279. doi: 10.2214/ajr.07.2165 CrossRefGoogle Scholar
  64. 64.
    Margenthaler JA, Duke D, Monsees BS, Barton PT, Clark C, Dietz JR (2006) Correlation between core biopsy and excisional biopsy in breast high-risk lesions. Am J Surg 192(4):534–537. doi: 10.1016/j.amjsurg.2006.06.003 PubMedCrossRefGoogle Scholar
  65. 65.
    Brem RF, Lechner MC, Jackman RJ, Rapelyea JA, Evans WP, Philpotts LE, Hargreaves J, Wasden S (2008) Lobular neoplasia at percutaneous breast biopsy: variables associated with carcinoma at surgical excision. Am J Roentgenol 190(3):637–641. doi: 10.2214/ajr.07.2768 CrossRefGoogle Scholar
  66. 66.
    Eby PR, Ochsner JE, DeMartini WB, Allison KH, Peacock S, Lehman CD (2009) Frequency and upgrade rates of atypical ductal hyperplasia diagnosed at stereotactic vacuum-assisted breast biopsy: 9-versus 11-gauge. Am J Roentgenol 192(1):229–234. doi: 10.2214/ajr.08.1342 CrossRefGoogle Scholar
  67. 67.
    Kohr JR, Eby PR, Allison KH, DeMartini WB, Gutierrez RL, Peacock S, Lehman CD (2010) Risk of upgrade of atypical ductal hyperplasia after stereotactic breast biopsy: effects of number of foci and complete removal of calcifications. Radiology 255(3):723–730. doi: 10.1148/radiol.09091406 PubMedCrossRefGoogle Scholar
  68. 68.
    Winchester DJ, Bernstein JR, Jeske JM, Nicholson MH, Hahn EA, Goldschmidt RA, Watkin WG, Sener SF, Bilimoria MB, Barrera E, Jr, Winchester DP (2003) Upstaging of atypical ductal hyperplasia after vacuum-assisted 11-gauge stereotactic core needle biopsy. Arch Surg 138(6):619–622. doi: 10.1001/archsurg.138.6.619 PubMedCrossRefGoogle Scholar
  69. 69.
    Ibrahim N, Bessissow A, Lalonde L, Mesurolle B, Trop I, Lisbona A, El-Khoury M (2012) Surgical outcome of biopsy-proven lobular neoplasia: is there any difference between lobular carcinoma in situ and atypical lobular hyperplasia? Am J Roentgenol 198(2):288–291. doi: 10.2214/ajr.11.7212 CrossRefGoogle Scholar
  70. 70.
    Tavassoli FA, Norris HJ (1990) A comparison of the results of long-term follow-up for atypical intraductal hyperplasia and intraductal hyperplasia of the breast. Cancer 65(3):518–529PubMedCrossRefGoogle Scholar
  71. 71.
    Marinho AF, Botelho M, Schmitt FC (2000) Evaluation of numerical abnormalities of chromosomes 1 and 17 in proliferative epithelial breast lesions using fluorescence in situ hybridization. Pathol Res Pract 196(4):227–233PubMedCrossRefGoogle Scholar
  72. 72.
    Krishnamurthy S, Zhao L, Hayes K, Glassman AB, Cristofanilli M, Singletary SE, Hunt KK, Kuerer HM, Sneige N (2004) Feasibility and utility of using chromosomal aneusomy to further define the cytologic categories in nipple aspirate fluid specimens: a preliminary study. Cancer 102(5):322–327PubMedCrossRefGoogle Scholar
  73. 73.
    Visscher DW, Wallis TL, Crissman JD (1996) Evaluation of chromosome aneuploidy in tissue sections of preinvasive breast carcinomas using interphase cytogenetics. Cancer 77(2):315–320PubMedCrossRefGoogle Scholar
  74. 74.
    King EB, Chew KL, Hom JD, Duarte LA, Mayall B, Miller TR, Neuhaus JM, Wrensch MR, Petrakis NL (1991) Characterization by image cytometry of duct epithelial proliferative disease of the breast. Mod Pathol 4(3):291–296PubMedGoogle Scholar
  75. 75.
    Schimmelpenning H, Eriksson ET, Falkmer UG, Azavedo E, Svane G, Auer GU (1992) Expression of the c-erbB-2 proto-oncogene product and nuclear DNA content in benign and malignant human breast parenchyma. Virchows Arch A 420(5):433–440CrossRefGoogle Scholar
  76. 76.
    Eriksson ET, Schimmelpenning H, Aspenblad U, Zetterberg A, Auer GU (1994) Immunohistochemical expression of the mutant p53 protein and nuclear DNA content during the transition from benign to malignant breast disease. Hum Pathol 25(11):1228–1233PubMedCrossRefGoogle Scholar
  77. 77.
    Carpenter R, Gibbs N, Matthews J, Cooke T (1987) Importance of cellular DNA content in pre-malignant breast disease and pre-invasive carcinoma of the female breast. Br J Surg 74(10):905–906PubMedCrossRefGoogle Scholar
  78. 78.
    Schmitt FC, Figueiredo P, Lacerda M (1995) Expression of c-erb B-2 protein and DNA ploidy in breast carcinogenesis. Arch Pathol Lab Med 119(9):815–820PubMedGoogle Scholar
  79. 79.
    Fabian CJ, Kimler BF, Zalles CM, Klemp JR, Kamel S, Zeiger S, Mayo MS (2000) Short-term breast cancer prediction by random periareolar fine-needle aspiration cytology and the Gail risk model. J Natl Cancer Inst 92(15):1217–1227PubMedCrossRefGoogle Scholar
  80. 80.
    Teplitz RL, Butler BB, Tesluk H, Min BH, Russell LA, Jensen HM, Hill LR (1990) Quantitative DNA patterns in human preneoplastic breast lesions. Anal Quant Cytol Histol 12(2):98–102PubMedGoogle Scholar
  81. 81.
    De Potter CR, Praet MM, Slavin RE, Verbeeck P, Roels HJ (1987) Feulgen DNA content and mitotic activity in proliferative breast disease. A comparison with ductal carcinoma in situ. Histopathology 11(12):1307–1319PubMedCrossRefGoogle Scholar
  82. 82.
    Dietrich CU, Pandis N, Teixeira MR, Bardi G, Gerdes AM, Andersen JA, Heim S (1995) Chromosome abnormalities in benign hyperproliferative disorders of epithelial and stromal breast tissue. Int J Cancer 60(1):49–53PubMedCrossRefGoogle Scholar
  83. 83.
    Aubele MM, Cummings MC, Mattis AE, Zitzelsberger HF, Walch AK, Kremer M, Hofler H, Werner M (2000) Accumulation of chromosomal imbalances from intraductal proliferative lesions to adjacent in situ and invasive ductal breast cancer. Diagn Mol Pathol 9(1):14–19PubMedCrossRefGoogle Scholar
  84. 84.
    Mastracci TL, Shadeo A, Colby SM, Tuck AB, O’Malley FP, Bull SB, Lam WL, Andrulis IL (2006) Genomic alterations in lobular neoplasia: a microarray comparative genomic hybridization signature for early neoplastic proliferationin the breast. Genes Chromosomes Cancer 45(11):1007–1017PubMedCrossRefGoogle Scholar
  85. 85.
    O’Connell P, Pekkel V, Fuqua SA, Osborne CK, Clark GM, Allred DC (1998) Analysis of loss of heterozygosity in 399 premalignant breast lesions at 15 genetic loci. J Natl Cancer Inst 90(9):697–703PubMedCrossRefGoogle Scholar
  86. 86.
    Lu YJ, Osin P, Lakhani SR, Di Palma S, Gusterson BA, Shipley JM (1998) Comparative genomic hybridization analysis of lobular carcinoma in situ and atypical lobular hyperplasia and potential roles for gains and losses of genetic material in breast neoplasia. Cancer Res 58(20):4721–4727PubMedGoogle Scholar
  87. 87.
    Tibiletti MG, Sessa F, Bernasconi B, Cerutti R, Broggi B, Furlan D, Acquati F, Bianchi M, Russo A, Capella C, Taramelli R (2000) A large 6q deletion is a common cytogenetic alteration in fibroadenomas, pre-malignant lesions, and carcinomas of the breast. Clin Cancer Res 6(4):1422–1431PubMedGoogle Scholar
  88. 88.
    Tidow N, Boecker A, Schmidt H, Agelopoulos K, Boecker W, Buerger H, Brandt B (2003) Distinct amplification of an untranslated regulatory sequence in the egfr gene contributes to early steps in breast cancer development. Cancer Res 63(6):1172–1178PubMedGoogle Scholar
  89. 89.
    Ellsworth RE, Ellsworth DL, Deyarmin B, Hoffman LR, Love B, Hooke JA, Shriver CD (2005) Timing of critical genetic changes in human breast disease. Ann Surg Oncol 12(12):1054–1060PubMedCrossRefGoogle Scholar
  90. 90.
    Chuaqui RF, Zhuang Z, Emmert-Buck MR, Liotta LA, Merino MJ (1997) Analysis of loss of heterozygosity on chromosome 11q13 in atypical ductal hyperplasia and in situ carcinoma of the breast. Am J Pathol 150(1):297–303PubMedPubMedCentralGoogle Scholar
  91. 91.
    Nayar R, Zhuang Z, Merino MJ, Silverberg SG (1997) Loss of heterozygosity on chromosome 11q13 in lobular lesions of the breast using tissue microdissection and polymerase chain reaction. Hum Pathol 28(3):277–282PubMedCrossRefGoogle Scholar
  92. 92.
    Tsuda H, Takarabe T, Akashi-Tanaka S, Fukutomi T, Hirohashi S (2001) Pattern of chromosome 16q loss differs between an atypical proliferative lesion and an intraductal or invasive ductal carcinoma occurring subsequently in the same area of the breast. Mod Pathol 14(5):382–388PubMedCrossRefGoogle Scholar
  93. 93.
    Mastracci TL, Tjan S, Bane AL, O’Malley FP, Andrulis IL (2005) E-cadherin alterations in atypical lobular hyperplasia and lobular carcinoma in situ of the breast. Mod Pathol 18(6):741–751PubMedCrossRefGoogle Scholar
  94. 94.
    Lakhani SR, Collins N, Stratton MR, Sloane JP (1995) Atypical ductal hyperplasia of the breast: clonal proliferation with loss of heterozygosity on chromosomes 16q and 17p. J Clin Pathol 48(7):611–615PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Kaneko M, Arihiro K, Takeshima Y, Fujii S, Inai K (2002) Loss of heterozygosity and microsatellite instability in epithelial hyperplasia of the breast. J Exp Ther Oncol 2(1):9–18PubMedCrossRefGoogle Scholar
  96. 96.
    Werner M, Mattis A, Aubele M, Cummings M, Zitzelsberger H, Hutzler P, Hofler H (1999) 20q13.2 amplification in intraductal hyperplasia adjacent to in situ and invasive ductal carcinoma of the breast. Virchows Arch 435(5):469–472PubMedCrossRefGoogle Scholar
  97. 97.
    Bean GR, Ibarra DC, Goldenberg VK, Baker JC Jr, Troch MM, Paisie C, Wilke LG, Yee L, Marcom PK, Kimler BF, Fabian CJ, Zalles CM, Broadwater G, Scott V, Seewaldt VL (2007) Hypermethylation of the breast cancer-associated gene 1 promoter does not predict cytologic atypia or correlate with surrogate end points of breast cancer risk. Cancer Epidemiol Biomarkers Prev 16(1):50–56PubMedCrossRefGoogle Scholar
  98. 98.
    Evron E, Dooley WC, Umbricht CB, Rosenthal D, Sacchi N, Gabrielson E, Soito AB, Hung DT, Ljung B, Davidson NE, Sukumar S (2001) Detection of breast cancer cells in ductal lavage fluid by methylation-specific PCR. Lancet 357(9265):1335–1336PubMedCrossRefGoogle Scholar
  99. 99.
    Umbricht CB, Evron E, Gabrielson E, Ferguson A, Marks J, Sukumar S (2001) Hypermethylation of 14-3-3 sigma (stratifin) is an early event in breast cancer. Oncogene 20(26):3348–3353PubMedCrossRefGoogle Scholar
  100. 100.
    van Hoesel AQ, Sato Y, Elashoff DA, Turner RR, Giuliano AE, Shamonki JM, Kuppen PJ, van de Velde CJ, Hoon DS (2013) Assessment of DNA methylation status in early stages of breast cancer development. Br J Cancer 108(10):2033–2038PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Liu T, Niu Y, Yu Y, Liu Y, Zhang F (2009) Increased gamma-tubulin expression and P16INK4A promoter methylation occur together in preinvasive lesions and carcinomas of the breast. Ann Oncol 20(3):441–448PubMedCrossRefGoogle Scholar
  102. 102.
    Liu T, Niu Y, Feng Y, Niu R, Yu Y, Lv A, Yang Y (2008) Methylation of CpG islands of p16(INK4a) and cyclinD1 overexpression associated with progression of intraductal proliferative lesions of the breast. Hum Pathol 39:1637–1646PubMedCrossRefGoogle Scholar
  103. 103.
    Visscher DW, Pankratz VS, Santisteban M, Reynolds C, Ristimaki A, Vierkant RA, Lingle WL, Frost MH, Hartmann LC (2008) Association between cyclooxygenase-2 expression in atypical hyperplasia and risk of breast cancer. J Natl Cancer Inst 100(6):421–427. doi: 10.1093/jnci/djn036 PubMedCrossRefGoogle Scholar
  104. 104.
    Weinstat-Saslow D, Merino MJ, Manrow RE, Lawrence JA, Bluth RF, Wittenbel KD, Simpson JF, Page DL, Steeg PS (1995) Overexpression of cyclin D mRNA distinguishes invasive and in situ breast carcinomas from non-malignant lesions. Nat Med 1(12):1257–1260PubMedCrossRefGoogle Scholar
  105. 105.
    Alle KM, Henshall SM, Field AS, Sutherland RL (1998) Cyclin D1 protein is overexpressed in hyperplasia and intraductal carcinoma of the breast. Clin Cancer Res 4(4):847–854PubMedGoogle Scholar
  106. 106.
    Zhu XL, Hartwick W, Rohan T, Kandel R (1998) Cyclin D1 gene amplification and protein expression in benign breast disease and breast carcinoma. Mod Pathol 11(11):1082–1088PubMedGoogle Scholar
  107. 107.
    Gatalica Z, Lele SM, Rampy BA, Norris BA (2000) The expression of Fhit protein is related inversely to disease progression in patients with breast carcinoma. Cancer 88(6):1378–1383PubMedCrossRefGoogle Scholar
  108. 108.
    Wang TT, Frezza EE, Ma R, Hu SY, Liu CZ, Zhang GY, Wachtel MS, Lu XM, Feng JB, Lu CX (2008) Loss expression of active fragile sites genes associated with the severity of breast epithelial abnormalities. Chin Med J 121(20):1969–1974PubMedGoogle Scholar
  109. 109.
    Xu R, Perle MA, Inghirami G, Chan W, Delgado Y, Feiner H (2002) Amplification of Her-2/neu gene in Her-2/neu-overexpressing and -nonexpressing breast carcinomas and their synchronous benign, premalignant, and metastatic lesions detected by FISH in archival material. Mod Pathol 15(2):116–124PubMedCrossRefGoogle Scholar
  110. 110.
    Eren F, Calay Z, Durak H, Eren B, Comunoglu N, Aydin O (2012) C-Erb-b2 oncogene expression in intraductal proliferative lesions of the breast. Bosnian J Basic Med Sci 12(1):41–50CrossRefGoogle Scholar
  111. 111.
    Mazzini RC, Elias S, Nazario AC, Kemp C, Logullo AF (2009) Prevalence of c-myc expression in breast lesions associated with microcalcifications detected by routine mammography. Sao Paulo Med J 127(2):66–70PubMedCrossRefGoogle Scholar
  112. 112.
    Gillett CE, Lee AH, Millis RR, Barnes DM (1998) Cyclin D1 and associated proteins in mammary ductal carcinoma in situ and atypical ductal hyperplasia. J Pathol 184(4):396–400PubMedCrossRefGoogle Scholar
  113. 113.
    Shi A, Dong J, Hilsenbeck S, Bi L, Zhang H, Li Y (2015) The status of STAT3 and STAT5 in human breast atypical ductal hyperplasia. PLoS ONE 10(7):e0132214PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Chin K, de Solorzano CO, Knowles D, Jones A, Chou W, Rodriguez EG, Kuo WL, Ljung BM, Chew K, Myambo K, Miranda M, Krig S, Garbe J, Stampfer M, Yaswen P, Gray JW, Lockett SJ (2004) In situ analyses of genome instability in breast cancer. Nat Genet 36(9):984–988PubMedCrossRefGoogle Scholar
  115. 115.
    Yashima K, Milchgrub S, Gollahon LS, Maitra A, Saboorian MH, Shay JW, Gazdar AF (1998) Telomerase enzyme activity and RNA expression during the multistage pathogenesis of breast carcinoma. Clin Cancer Res 4(1):229–234PubMedGoogle Scholar
  116. 116.
    Song M, Mi X, Li B, Zhu J, Gao Y, Cui S, Song J (2002) Expression of telomerase genes in cancer development in atypical hyperplasia of the mammary duct. Chin Med J 115(8):1221–1225PubMedGoogle Scholar
  117. 117.
    Guan H, Sun Y, Zan Q, Xu M, Li Y, Zhou J, He E, Eriksson S, Wen W, Skog S (2009) Thymidine kinase 1 expression in atypical ductal hyperplasia significantly differs from usual ductal hyperplasia and ductal carcinoma in situ: a useful tool in tumor therapy management. Mol Med Rep 2(6):923–929PubMedGoogle Scholar
  118. 118.
    Rosenberg CL, Larson PS, Romo JD, de las MA, Faller DV (1997) Microsatellite alterations indicating monoclonality in atypical hyperplasias associated with breast cancer. Hum Pathol 28(2):214–219PubMedCrossRefGoogle Scholar

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© The Author(s) 2017

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Authors and Affiliations

  1. 1.Surgery BranchCenter for Cancer Research, National Cancer Institute, National Institutes of HealthBethesdaUSA

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