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Modelling the Molecular Pathology of Breast Cancer Initiation

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Precision Molecular Pathology of Breast Cancer

Part of the book series: Molecular Pathology Library ((MPLB,volume 10))

Abstract

To really understand the molecular pathology of breast cancers and their initiation, it is necessary to have valid models. These models not only need to take into account the diversity of breast cancers, but also the roles of other cells, either via secreted factors and/or direct contact, found in the breast. The cell lines that are available can to a degree reflect the heterogeneity of breast cancers, but by virtue of their immortality and the methods used to achieve this, can never be truly representative of ‘real breast cancer’. The validity of breast cancer models can also be improved by consideration of 3D systems in which the other elements of the breast, in addition to the malignant epithelium, are used, notably myoepithelial cells and fibroblasts. In this way, not only can the morphological elements of breast cancer be more faithfully reduplicated, but also potentially the underlying molecular pathology. It remains true that no single model is perfect and studies using these are best done hand in hand with clinical studies.

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References

  1. Curtis C, et al. The genomic and transcriptomic architecture of 2000 breast tumours reveals novel subgroups. Nature. 2012;486(7403):346–52.

    PubMed Central  CAS  PubMed  Google Scholar 

  2. Lehmann BD, et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Investig. 2011;121(7):2750–67.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Sørlie T, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U.S.A. 2001;98(19):10869–74.

    Article  PubMed Central  PubMed  Google Scholar 

  4. Eccles SA, et al. Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer. Breast Cancer Res. 2013;15:5.

    Google Scholar 

  5. Wellings SR, Jensen HM, Marcum RG. An atlas of subgross pathology of the human breast with special reference to possible precancerous lesions. J Natl Cancer Inst. 1975;55(2):231–73.

    CAS  PubMed  Google Scholar 

  6. Carley AM, et al. Frequency and clinical significance of simultaneous association of lobular neoplasia and columnar cell alterations in breast tissue specimens. Am J Clin Pathol. 2008;130(2):254–8.

    Article  CAS  PubMed  Google Scholar 

  7. Abdel-Fatah TM, et al. High frequency of coexistence of columnar cell lesions, lobular neoplasia, and low grade ductal carcinoma in situ with invasive tubular carcinoma and invasive lobular carcinoma. Am J Surg Pathol. 2007;31(3):417–26.

    Article  PubMed  Google Scholar 

  8. Abdel-Fatah TM, et al. Morphologic and molecular evolutionary pathways of low nuclear grade invasive breast cancers and their putative precursor lesions: further evidence to support the concept of low nuclear grade breast neoplasia family. Am J Surg Pathol. 2008;32(4):513–23.

    Article  PubMed  Google Scholar 

  9. Dabbs DJ, et al. Molecular alterations in columnar cell lesions of the breast. Mod Pathol. 2006;19(3):344–9.

    Article  CAS  PubMed  Google Scholar 

  10. Moinfar F, et al. Concurrent and independent genetic alterations in the stromal and epithelial cells of mammary carcinoma: implications for tumorigenesis. Cancer Res. 2000;60(9):2562–6.

    CAS  PubMed  Google Scholar 

  11. Simpson PT, et al. Columnar cell lesions of the breast: the missing link in breast cancer progression? A morphological and molecular analysis. Am J Surg Pathol. 2005;29(6):734–46.

    Article  PubMed  Google Scholar 

  12. Aubele MM, et al. Accumulation of chromosomal imbalances from intraductal proliferative lesions to adjacent in situ and invasive ductal breast cancer. Diagn Mol Pathol. 2000;9(1):14–9.

    Article  CAS  PubMed  Google Scholar 

  13. Perou CM, et al. Molecular portraits of human breast tumours. Nature. 2000;406(6797):747–52.

    Article  CAS  PubMed  Google Scholar 

  14. Forozan F, et al. Comparative genomic hybridization analysis of 38 breast cancer cell lines: a basis for interpreting complementary DNA microarray data. Cancer Res. 2000;60(16):4519–25.

    CAS  PubMed  Google Scholar 

  15. Weigelt B, Bissell M. Unraveling the microenvironmental influences on the normal mammary gland and breast cancer. Semin Cancer Biol. 2008;18(5):311–21.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Matthay MA, et al. Transient effect of epidermal growth factor on the motility of an immortalized mammary epithelial cell line. J Cell Sci. 1993;106(Pt 3):869–78.

    CAS  PubMed  Google Scholar 

  17. Soule HD, et al. Isolation and characterization of a spontaneously immortalized human breast epithelial cell line, MCF-10. Cancer Res. 1990;50(18):6075–86.

    CAS  PubMed  Google Scholar 

  18. Tait L, Soule HD, Russo J. Ultrastructural and immunocytochemical characterization of an immortalized human breast epithelial cell line, MCF-10. Cancer Res. 1990;50(18):6087–94.

    CAS  PubMed  Google Scholar 

  19. DiRenzo J, et al. Growth factor requirements and basal phenotype of an immortalized mammary epithelial cell line. Cancer Res. 2002;62(1):89–98.

    CAS  PubMed  Google Scholar 

  20. Yusuf R, Frenkel K. Morphologic transformation of human breast epithelial cells MCF-10A: dependence on an oxidative microenvironment and estrogen/epidermal growth factor receptors. Cancer Cell Int. 2010;10(1):30.

    Article  PubMed Central  PubMed  Google Scholar 

  21. Marella NV, et al. Cytogenetic and cDNA microarray expression analysis of MCF10 human breast cancer progression cell lines. Cancer Res. 2009;69(14):5946–53.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Bartek J, et al. Efficient immortalization of luminal epithelial cells from human mammary gland by introduction of simian virus 40 large tumor antigen with a recombinant retrovirus. Proc Natl Acad Sci U.S.A. 1991;88(9):3520–4.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Caradonna F, Luparello C. Cytogenetic characterization of HB2 epithelial cells from the human breast. In Vitro Cell Dev Biol Anim. 2014;50(1):48–55.

    Article  PubMed  Google Scholar 

  24. Miller FR, et al. MCF10DCIS.com xenograft model of human comedo ductal carcinoma in situ. J Natl Cancer Inst. 2000;92(14):1185–6.

    Article  CAS  PubMed  Google Scholar 

  25. Forozan F, et al. Molecular cytogenetic analysis of 11 new breast cancer cell lines. Br J Cancer. 1999;81(8):1328–34.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Bissell MJ, Radisky D. Putting tumours in context. Nat Rev Cancer. 2001;1(1):46–54.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Cukierman E, Pankov R, Yamada KM. Cell interactions with three-dimensional matrices. Curr Opin Cell Biol. 2002;14(5):633–9.

    Article  CAS  PubMed  Google Scholar 

  28. Zwezdaryk KJ, et al. Rotating cell culture systems for human cell culture: human trophoblast cells as a model. J Vis Exp. 2012;18:59.

    Google Scholar 

  29. Foty R. A simple hanging drop cell culture protocol for generation of 3D spheroids. J Vis Exp. 2011;51:2720. doi: 10.3791/2720.

  30. Naber HP. Spheroid assay to measure TGF-beta-induced invasion. J Vis Exp. 2011;16(57):3337.

    Google Scholar 

  31. Nagelkerke A, et al. Hypoxia stimulates migration of breast cancer cells via the PERK/ATF4/LAMP3-arm of the unfolded protein response. Breast Cancer Res. 2013;15(1):R2.

    Google Scholar 

  32. Ivascu A, Kubbies M. Rapid generation of single-tumor spheroids for high-throughput cell function and toxicity analysis. J Biomol Screen. 2006;11(8):922–32.

    Article  CAS  PubMed  Google Scholar 

  33. Zhang X, et al. Development of an in vitro multicellular tumor spheroid model using microencapsulation and its application in anticancer drug screening and testing. Biotechnol Prog. 2005;21(4):1289–96.

    Article  CAS  PubMed  Google Scholar 

  34. Smart CE, et al. In vitro analysis of breast cancer cell line tumourspheres and primary human breast epithelia mammospheres demonstrates inter- and intrasphere heterogeneity. PLoS ONE. 2013;8(6):e64388.

    Google Scholar 

  35. Farnie G, et al. Novel cell culture technique for primary ductal carcinoma in situ: role of Notch and epidermal growth factor receptor signaling pathways. J Natl Cancer Inst. 2007;99(8):616–27.

    Article  CAS  PubMed  Google Scholar 

  36. Shaw FL, et al. A detailed mammosphere assay protocol for the quantification of breast stem cell activity. J Mammary Gland Biol Neoplasia. 2012;17(2):111–7.

    Article  PubMed  Google Scholar 

  37. Leeper AD, et al. Long-term culture of human breast cancer specimens and their analysis using optical projection tomography. J Vis Exp. 2011;29(53).

    Google Scholar 

  38. Holliday DL, et al. Novel multicellular organotypic models of normal and malignant breast: tools for dissecting the role of the microenvironment in breast cancer progression. Breast Cancer Res. 2009;11(1):R3.

    Article  PubMed Central  PubMed  Google Scholar 

  39. Debnath J, Brugge JS. Modelling glandular epithelial cancers in three-dimensional cultures. Nat Rev Cancer. 2005;5(9):675–88.

    Article  CAS  PubMed  Google Scholar 

  40. Debnath J, Muthuswamy SK, Brugge JS. Morphogenesis and oncogenesis of MCF-10A mammary epithelial acini grown in three-dimensional basement membrane cultures. Methods. 2003;30(3):256–68.

    Article  CAS  PubMed  Google Scholar 

  41. Streuli CH, Bailey N, Bissell MJ. Control of mammary epithelial differentiation: basement membrane induces tissue-specific gene expression in the absence of cell-cell interaction and morphological polarity. The Journal of Cell Biology. 1991;115(5):1383–95.

    Article  CAS  PubMed  Google Scholar 

  42. Wisdom BJ, et al. Type IV collagen of Engelbreth-Holm-Swarm tumor matrix: identification of constituent chains. Connect Tissue Res. 1992;27(4):225–34.

    Article  PubMed  Google Scholar 

  43. Vaillant F, Lindeman G, Visvader J. Jekyll or Hyde: does Matrigel provide a more or less physiological environment in mammary repopulating assays? Breast Cancer Res. 2011;13(3):108.

    Article  PubMed Central  PubMed  Google Scholar 

  44. Parmar H, Cunha GR. Epithelial-stromal interactions in the mouse and human mammary gland in vivo. Endocr Relat Cancer. 2004;11(3):437–58.

    Article  CAS  PubMed  Google Scholar 

  45. Provenzano P, et al. Collagen reorganization at the tumor-stromal interface facilitates local invasion. BMC Med. 2006;4(1):38.

    Article  PubMed Central  PubMed  Google Scholar 

  46. Provenzano PP, et al. Matrix density-induced mechanoregulation of breast cell phenotype, signaling and gene expression through a FAK-ERK linkage. Oncogene. 2009;28(49):4326–43.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  47. Dhimolea E, et al. The role of collagen reorganization on mammary epithelial morphogenesis in a 3D culture model. Biomaterials. 2010;31(13):3622–30.

    Article  CAS  PubMed  Google Scholar 

  48. Maskarinec G, et al. Mammographic density as a predictor of breast cancer survival: the Multiethnic Cohort. Breast Cancer Res. 2013;15(1):R7.

    Google Scholar 

  49. Alowami S, et al. Mammographic density is related to stroma and stromal proteoglycan expression. Breast Cancer Res. 2003;5(5):R129–35.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Krause S, et al. A novel 3D in vitro culture model to study stromal-epithelial interactions in the mammary gland. Tissue Eng Part C Methods. 2008;14(3):261–71.

    Article  CAS  PubMed  Google Scholar 

  51. Berdichevsky F, et al. Branching morphogenesis of human mammary epithelial cells in collagen gels. J Cell Sci. 1994;107(12):3557–68.

    CAS  PubMed  Google Scholar 

  52. O’Brien LE, et al. Morphological and biochemical analysis of Rac1 in three-dimensional epithelial cell cultures. Methods Enzymol. 2006;406:676–91.

    Article  PubMed  Google Scholar 

  53. Dickinson ME. Multimodal imaging of mouse development: tools for the postgenomic era. Dev Dyn. 2006;235(9):2386–400.

    Article  PubMed  Google Scholar 

  54. Kubow KE, Horwitz AR. Reducing background fluorescence reveals adhesions in 3D matrices. Nat Cell Biol. 2011;13(1):3–5.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  55. Zipfel WR, Williams RM, Webb WW. Nonlinear magic: multiphoton microscopy in the biosciences. Nat Biotechnol. 2003;21(11):1369–77.

    Article  CAS  PubMed  Google Scholar 

  56. Huang D, et al. Optical coherence tomography. Science. 1991;254(5035):1178–81.

    Article  CAS  PubMed  Google Scholar 

  57. Sharpe J, et al. Optical projection tomography as a tool for 3D microscopy and gene expression studies. Science. 2002;296(5567):541–5.

    Article  CAS  PubMed  Google Scholar 

  58. Sameni M, et al. MAME models for 4D live-cell imaging of tumor: microenvironment interactions that impact malignant progression. J Vis Exp. 2012;17(60):3661.

    Google Scholar 

  59. Petersen OW, et al. Interaction with basement membrane serves to rapidly distinguish growth and differentiation pattern of normal and malignant human breast epithelial cells. Proc Natl Acad Sci U.S.A. 1992;89(19):9064–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  60. Krause S, et al. A novel 3D in vitro culture model to study stromal-epithelial interactions in the mammary gland. Tissue Eng Part C: Methods. 2008;14(3):261–71.

    Article  CAS  Google Scholar 

  61. Shekhar MPV, Werdell J, Tait L. Interaction with endothelial cells is a prerequisite for branching ductal-alveolar morphogenesis and hyperplasia of preneoplastic human breast epithelial cells: regulation by estrogen. Cancer Res. 2000;60(2):439–49.

    CAS  PubMed  Google Scholar 

  62. Wang X, et al. Preadipocytes stimulate ductal morphogenesis and functional differentiation of human mammary epithelial cells on 3D silk scaffolds. Tissue Eng Part A. 2009;15(10):3087–98.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  63. Olsen C, et al. Human mammary fibroblasts stimulate invasion of breast cancer cells in a three-dimensional culture and increase stroma development in mouse xenografts. BMC Cancer. 2010;10(1):444.

    Article  PubMed Central  PubMed  Google Scholar 

  64. Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer. 2002;2(3):161–74.

    Article  CAS  PubMed  Google Scholar 

  65. Gilles C, et al. Implication of collagen type 1-induced membrane-type 1 matrix metalloproteinase expression and matrix metalloproteinase-2 activation in the metastatic progression of breast carcinoma. Lab Invest. 1997;76(5):651–60.

    CAS  PubMed  Google Scholar 

  66. Barsky SH. Myoepithelial mRNA expression profiling reveals a common tumor-suppressor phenotype. Exp Mol Pathol. 2003;74(2):113–22.

    Article  CAS  PubMed  Google Scholar 

  67. Jones JL, et al. Primary breast myopithelial cells exert an invasion-suppressor effect on breast cancer cells via paracrine down-regulation of MMP expresssion in fibroblasts and tumour cells. J Pathol. 2003;201(4):562–72.

    Article  CAS  PubMed  Google Scholar 

  68. Gudjonsson T, et al. Normal and tumor-derived myoepithelial cells differ in their ability to interact with luminal breast epithelial cells for polarity and basement membrane deposition. J Cell Sci. 2002;115(1):39–50.

    PubMed Central  CAS  PubMed  Google Scholar 

  69. Jeanes AI, Maya-Mendoza A, Streuli CH. Cellular microenvironment influences the ability of mammary epithelia to undergo cell cycle. PLoS ONE. 2011;6(3):e18144.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. St. James University Hospital/University of Leeds, Leeds Institute of Cancer and Pathology (LICAP), Beckett Street, LS9 7TF, Leeds, West Yorkshire, UK

    Claire Nash, Andrew M. Hanby & Valerie Speirs

Authors
  1. Claire Nash
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  2. Andrew M. Hanby
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  3. Valerie Speirs
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Corresponding author

Correspondence to Andrew M. Hanby .

Editor information

Editors and Affiliations

  1. Department of Pathology, University of Massachusetts Medical School, UMassMemorial Medical Center, Worcester, Massachusetts, USA

    Ashraf Khan

  2. Department of Histopathology, University of Nottingham, Nottingham, United Kingdom

    Ian O. Ellis

  3. Leeds Institute of Cancer and Pathology, St. James University Hospital, Leeds, West Yorkshire, United Kingdom

    Andrew M. Hanby

  4. Department of Pathology, University of Massachusetts Medical School, UMassMemorial Medical Center, Worcester, Massachusetts, USA

    Ediz F. Cosar

  5. Department of Histopathology, University of Nottingham, Nottingham, United Kingdom

    Emad A. Rakha

  6. Department of Pathology, University of Massachusetts Medical School, UMassMemorial Medical Center, Worcester, Massachusetts, USA

    Dina Kandil

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Nash, C., Hanby, A.M., Speirs, V. (2015). Modelling the Molecular Pathology of Breast Cancer Initiation. In: Khan, A., Ellis, I., Hanby, A., Cosar, E., Rakha, E., Kandil, D. (eds) Precision Molecular Pathology of Breast Cancer. Molecular Pathology Library, vol 10. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-2886-6_3

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  • DOI: https://doi.org/10.1007/978-1-4939-2886-6_3

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