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ID2 and GJB2 promote early-stage breast cancer progression by regulating cancer stemness

  • Yin Liu
  • Puspa R. Pandey
  • Sambad Sharma
  • Fei Xing
  • Kerui Wu
  • Amar Chittiboyina
  • Shih-Ying Wu
  • Abhishek Tyagi
  • Kounosuke WatabeEmail author
Preclinical study
  • 30 Downloads

Abstract

Purpose

Ductal carcinoma in situ (DCIS) is a non-invasive form of breast cancer which could progress to or recur as invasive breast cancer. The underlying molecular mechanism of DCIS progression is yet poorly understood, and appropriate biomarkers to distinguish benign form of DCIS from potentially invasive tumor are urgently needed.

Methods

To identify the key regulators of DCIS progression, we performed gene-expression analysis of syngeneic breast cancer cell lines MCF10A, DCIS.com, and MCF10CA and cross-referenced the targets with patient cohort data.

Results

We identified ID2 as a critical gene for DCIS initiation and found that ID2 promoted DCIS formation by enhancing cancer stemness of pre-malignant cells. ID2 also plays a pivotal role in survival of the aggressive cancer cells. In addition, we identified INHBA and GJB2 as key regulators for the transition of benign DCIS to aggressive phenotype. These two genes regulate migration, colonization, and stemness of invasive cancer cells. Upregulation of ID2 and GJB2 predicts poor prognosis after breast-conserving surgery. Finally, we found a natural compound Helichrysetin as ID2 inhibitor which suppresses DCIS formation in vitro and in vivo.

Conclusion

Our results indicate that ID2 is a key driver of DCIS formation and therefore is considered to be a potential target for prevention of DCIS, while INHBA and GJB2 play vital roles in progression of DCIS to IDC and they may serve as potential prognosis markers.

Keywords

Breast cancer DCIS IDC Cancer prevention 

Abbreviations

DCIS

Ductal carcinoma in situ

IDC

Invasive ductal carcinoma

CI

Confidence interval

ID2

Inhibitor of DNA binding 2

INHBA

Inhibin beta A subunit

GJB2

Gap junction protein beta 2

SOX2

SRY-Box 2

ZEB

Zinc Finger E-Box Binding Homeobox

BMP7

Bone Morphogenetic Protein 7

TGF-β

Transforming Growth Factor Beta

TWIST

Twist Family BHLH Transcription Factor

TCGA

The cancer genome atlas

Notes

Acknowledgements

We thank Dr. Fariba Behbod for the Sum225 cell line.

Funding

This study was funded by This work was supported by NIH grant R01CA173499, R01CA185650, and R01CA205067 to K.W, a pilot grant from Comprehensive Cancer Center of Wake Forest University to F.X. Y.L. is supported by NIH fellowship F31CA200286. The Tumor Tissue and Pathology Shared Resources, and Biostatistics/Bioinformatics Shared Resource are supported by the Comprehensive Cancer Center of Wake Forest University NCI, National Institutes of Health Grant (P30CA012197).

Compliance with ethical standards

Conflict of interest

all of the authors declare no conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. This article does not contain any studies with human participants by any of the authors.

Supplementary material

10549_2018_5126_MOESM1_ESM.xlsx (13.7 mb)
Supplementary material 1 (XLSX 14029 KB)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Cancer BiologyWake Forest School of MedicineWinston SalemUSA
  2. 2.Department of Medical Microbiology, Immunology & Cell BiologySouthern Illinois University School of MedicineSpringfieldUSA
  3. 3.School of PharmacyUniversity of MississippiOxfordUSA
  4. 4.Lonza Walkersville, IncWalkersvilleUSA

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