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Breast cancer epigenetics: normal human mammary epithelial cells as a model system

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Abstract

DNA hypermethylation and histone modifications are two critical players involved in epigenetic regulation and together play an important role in silencing tumor-suppressor genes in all cancers, including breast cancer. One of the major challenges facing breast cancer researchers is the problem of how to identify critical genes that are epigenetically silenced early in cancer initiation as these genes provide potential early diagnostic and/or therapeutic targets for breast cancer management. This review will focus on compelling evidence that normal Human Mammary Epithelial Cells (HMECs) that escape senescence in culture mimic genetic and epigenetic events occurring in early breast cancer, and provide a valuable system to delineate the early steps in epigenetic deregulation that often occur during transition of a normal breast cell to a premalignant cell. In particular, this model system has been used to investigate the relationship between gene silencing, DNA methylation, histone modifications, and polycomb association that may occur early in oncogenic transformation.

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Abbreviations

bp:

base pairs

BMI-1:

B lymphoma Mo-MLV insertion region

BRCA1 :

breast cancer 1, early onset

CDKN2A :

cyclin dependent kinase inhibitor 2A

ChIP:

chromatin immunoprecipitation

Cox-2 :

cyclo-oxygenase 2

DNA:

deoxyribonucleic acid

DNMT:

DNA methyltransferase

EZH2:

enhancer of zeste homolog 2

H:

histone

HDAC:

histone deacetylase

HMEC:

human mammary epithelial cells

HMT:

histone methyltransferase

K:

lysine

kb:

kilobases

MBD:

methyl-C binding domain

MeCP2:

methyl CpG binding protein 2

PcG:

polycomb group

PRC:

polycomb repressive complex

Rb :

retinoblastoma 1

SUZ12:

suppressor of zeste 12

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Acknowledgments

RAH is supported by a Dora Lush Biomedical Postgraduate Scholarship from the National Health and Medical Research Council (NH&MRC) and in part by a Cancer Institute NSW (CI NSW) Research Scholar Award and a National Breast Cancer Foundation (NBCF) Excellence Award. SJC is supported by an NH&MRC fellowship and NH&MRC project grants.

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    Rebecca A. Hinshelwood & Susan J. Clark

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  1. Rebecca A. Hinshelwood
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Correspondence to Susan J. Clark.

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Hinshelwood, R.A., Clark, S.J. Breast cancer epigenetics: normal human mammary epithelial cells as a model system. J Mol Med 86, 1315–1328 (2008). https://doi.org/10.1007/s00109-008-0386-3

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  • DOI: https://doi.org/10.1007/s00109-008-0386-3

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