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Project 3 - Epigenetics in Breast Cancer Risk and Tumor Development

Pregnancy study

Human epidemiological and experimental data in rodent models suggest that full-term pregnancy in early adulthood decreases the risk of estrogen receptor positive (ER+) breast cancer in post-menopausal women; however, the underlying mechanism is largely unknown. We hypothesized that the cancer-preventive effects of parity may be due to alterations in the number or properties of mammary epithelial progenitor/stem cells that are thought to be the cell-of-origin of breast cancer, rendering them less susceptible to oncogenesis. To test this hypothesis, we analyzed the relative frequency and comprehensive molecular profiles of four distinct cell types (CD24+ luminal, CD10+ myoepithelial, lin-/CD24-/CD44+ progenitor-enriched, and stromal fibroblasts) isolated from normal breast tissue of premenopausal nulliparous and parous women. Based on the comprehensive analysis of gene expression, DNA, and histone H3 K27 trimethylation profiles of these cell types, we determined that the most significant changes occurred in lin-/CD24-/CD44+ progenitor-enriched cells. The activity of many genes and pathways involved in development, differentiation, and cell cycle regulation are decreased in parous women that may contribute to their decreased breast cancer risk. We also identified a parity-associated gene signature that predicted clinical outcome in breast cancer patients diagnosed with ER+ tumors.

The role of DNA methylation in mouse mammary gland development

The mouse mammary gland is a useful model system for understanding factors that regulate mammary development. We are pursuing molecular characterization of the different cell types that comprise the mammary epithelium of the mouse. Based on the varying proportional distributions we observe in the mature, progenitor, and stem cell populations of the mammary gland during different life stages, we seek to understand the underlying molecular cues that maintain cell type identities and direct cellular distribution changes by studying the gene expression and epigenetic properties of distinct cell populations during puberty and pregnancy, stages during which there is dramatic tissue remodeling in the mammary gland. Furthermore, with the use of in vitro and in vivo mouse models for the functional characterization of maintenance DNA methylation, we are characterizing potential active roles of this important epigenetic mark in directing cell fate in the mammary gland.

Histone modifying enzymes as new therapeutic targets

The differentiation of normal stem cells and the development of normal tissue are controlled by epigenetic mechanisms. Abnormalities in these processes play a role in the initiation and progression of tumors and intra-tumor diversification of cancer cells. A number of histone-modifying genes were found to be mutated in breast and other cancers, implying that these genes may represent novel therapeutic targets and biomarkers. We have recently reported the characterization of cell-type specific patterning of histone and DNA methylation in normal breast tissues. We developed modified chromatin immunoprecipitation combined with high-throughput sequencing (ChIP-Seq) protocol which enables us to investigate the epigenetic status genome-wide, using limited numbers of cells purified from human breast tissue samples. Currently, we are using various genomic profiling and functional studies to validate several histone demethylases as potential therapeutic targets in breast cancer.

Determinants of basal-like and luminal breast cancer cell phenotypes

Basal-like and luminal breast tumors have distinct molecular profiles and clinical behavior, yet the mechanisms underlying these differences are poorly defined. We investigated the potential role of genetic factors in determining these distinct phenotypes and their inheritance pattern by generating somatic cell fusions between basal-like and luminal breast cancer cells and analyzing their molecular profiles and functional characteristics. Based on the molecular profiles, we identified candidate key transcriptional and epigenetic determinants of basal-like and luminal cell phenotypes. We are further characterizing these genes using functional genomics approaches.

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