In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 3567-3567
Abstract:
Estrogens and progesterone (PROG) are key mediators of breast cancer aetiology and progression. The predominant actions of these hormones in the breast are mediated via their respective cognate steroid receptors, estrogen receptor alpha (ERα) and progesterone receptor (PGR). As ERα upregulates PGR expression, both are currently measured in clinical breast cancer samples to determine the utility of anti-estrogen therapy. Although the molecular actions of estrogens have been extensively studied, the role of PROG and PGR need further elucidation, particularly in the context of activated ERα signaling. Here, we treated ZR75-1 cells with 17β-estradiol (E2) alone or in combination with PROG and assessed global transcriptional responses by microarray expression profiling and receptor binding profiles by chromatin immunoprecipitation-sequencing (ChIP-seq). PROG treatment alone significantly altered the regulation of only seven genes, whereas long term E2 treatment increased the PROG transcriptional response altering 785 genes (p value ≤ 0.05), and regulated pathways involved in ErbB signalling and cell proliferation. Consistent with these findings, ChIP-seq identified 10 times more PGR binding sites following long term E2 treatment (4566 at equivalent peak threshold) compared with PROG treatment alone. Candidate PGR ChIP validated these findings at 100% (12/12) sites tested. The long term E2-treated PGR cistrome was highly conserved amongst species, and enriched for progesterone receptor response elements (PREs) and FOXA1 binding sites. E2 enhancement of PGR binding could be abrogated by long term (72h) but not short term (4h) tamoxifen co-treatment. In T-47D cells, long term E2 treatment was not required for efficient interaction of PGR with DNA and FOXA1 silencing resulted in decreased PGR DNA occupancy at several sites. These data suggests that the combination of E2 and PROG regulated a distinct transcriptional response in breast cancer cells, perhaps due to the dependence of PGR on E2 signaling for maintenance of cellular PGR levels, and via the receptors sharing mutual collaborators and coregulators, such as FOXA1. ERα and PGR collectively shape a mitogenic response in breast cancer cells that is dependent on the combined presence of E2 and PROG. Citation Format: Erin E. Swinstead, Andrew P. Trotta, Eric Smith, Phulwinder K. Grover, Eleanor F. Need, Grant Buchanan. Estrogen signaling promotes effective progesterone receptor engagement with DNA in breast cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3567. doi:10.1158/1538-7445.AM2013-3567
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2013-3567
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2013
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
Permalink
