Estrogen-Estrogen Receptor axis in non-transformed breast epithelial cells: studies beyond MCF-7

Project: Research project

Project Details

Description

? DESCRIPTION (provided by applicant): Estrogen (E2) acting through the nuclear receptor estrogen receptor alpha (ER?) plays a major role in breast cancer. Approximately 70% of breast cancers express ER? and patients with ER?-positive breast cancers receive anti-estrogens. However, resistance to anti-estrogen therapy is a major clinical problem. There are at least two critical unresolved issues in this field: 1) in the normal breast, ER? is expressed in 10-20% of non- dividing cells. These ER?-positive cells support proliferation of ER?-negative cells in response to E2 through paracrine action. In contrast to normal cells, ER?-positive cancer cells themselves proliferate in response to E2. Mechanisms governing switch in this ER? function are largely unknown and is the focus of this proposal; 2) Mechanisms of anti-estrogen resistance. Most of our current knowledge of ER? biology including genome- wide binding pattern (ER? cistrome), the role of pioneer factors/chromatin modifications in guiding ER? cistrome, and E2-regulated gene expression pattern (E2-transcriptome) are from studies using the cancer cell line MCF-7 but not normal/non-transformed cells because it has not been technically possible to culture ER?- expressing non-transformed cells. This limitation has prevented us from understanding the function of ER? in the normal breast and mechanisms that govern cancer-associated shift in ER? function. To address these critical issues, we generated several ER?-positive breast epithelial cell lines by propagating cells from normal breast using recently described epithelial cell-reprogramming assay followed by immortalization using the hTERT. Consistent with the predicted expression pattern of ER? in primary cells, ER? is expressed in the luminal progenitor and mature cell but not in stem cell fraction of these cell lines, which authenticates the relevance of the system. RNA-seq analysis of one of these cell lines showed dominant action of ER?:E2 in repressing gene expression. In contrast, ER?-signaling involved both activation and repression in cancer cells and was well integrated with PI3K-Cyclin D1-cMyc proliferation network as well as an atypical ubiquitination system not seen in normal cells. Using these new resources, we will address the hypothesis that switch in ER? cistrome and E2-transciptome from a repressor mode to a activator mode is a critical early step in ER?- positive breast cancer. The specific aims are to: 1) Define ER? cistrome that is unique to non-transformed breast epithelial cells; 2) Investigate signaling nodes that govern ER? function in non-transformed and transformed breast epithelial cells by integrating ER? cistrome with transcriptome. Impact: To our knowledge, this is the first study to determine ER? function in non-transformed breast epithelial cells. The resources developed will be valuable to the research community to reassess signaling networks associated with ER?-positive breast cancer and anti-estrogen resistance. In particular, signaling defects linked to genomic aberrations uniquely enriched in ER?-positive breast cancers can be investigated and drugs targeting specific aberration can be identified using this resource.
StatusFinished
Effective start/end date12/4/1511/30/17

Funding

  • National Institutes of Health: $78,000.00

ASJC

  • Medicine(all)

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