Estrogen receptor-α (ERα) mediates the essential biological function of estrogen in breast development and tumorigenesis. Multiple mechanisms, including pioneer factors, coregulators and epigenetic modifications have been identified as regulators of ERα signaling in breast cancer. However, previous studies of ERα regulation have focused on luminal and HER2-positive subtypes rather than basal-like breast cancer (BLBC), in which ERα is underexpressed. In addition, mechanisms that account for the decrease or loss of ER expression in recurrent tumors after endocrine therapy remain elusive. Here, we demonstrate a novel FOXC1-driven mechanism that suppresses ERα expression in breast cancer. We find that FOXC1 competes with GATA-binding protein 3 (GATA3) for the same binding regions in the cis-regulatory elements upstream of the ERα gene and thereby downregulates ERα expression and consequently its transcriptional activity. The forkhead domain of FOXC1 is essential for the competition with GATA3 for DNA binding. Counteracting the action of GATA3 at the ERα promoter region, overexpression of FOXC1 hinders recruitment of RNA polymerase II and increases histone H3K9 trimethylation at ERα promoters. Importantly, ectopic FOXC1 expression in luminal breast cancer cells reduces sensitivity to estrogen and tamoxifen. Furthermore, in breast cancer patients with ER-positive primary tumors who received adjuvant tamoxifen treatment, FOXC1 expression is associated with decreased or undetectable ER expression in recurrent tumors. Our findings highlight a clinically relevant mechanism that contributes to the low or absent ERα expression in BLBC. This study suggests a new paradigm to study ERα regulation during breast cancer progression and indicates a role of FOXC1 in the modulation of cellular response to endocrine treatment.
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We thank Dr Julia Gee for discussion about antiestrogen experiments. This work was supported by the National Institutes of Health (CA151610), the Avon Foundation for Women (02-2014-063) and David Salomon Translational Breast Cancer Research Fund, and Eleanor and Glenn Padnick Discovery Fund in Cellular Therapy to Xiaojiang Cui, the Fashion Footwear Charitable Foundation of New York, Inc., associates for Breast and Prostate Cancer Studies, the Margie and Robert E. Petersen Foundation, and the Linda and Jim Lippman Research Fund to Armando Giuliano.
Xiaojiang Cui is a named inventor for patent applications regarding the role of FOXC1 in cancer. The remaining authors declare no conflict of interest.
Supplementary Information accompanies this paper on the Oncogene website
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Yu-Rice, Y., Jin, Y., Han, B. et al. FOXC1 is involved in ERα silencing by counteracting GATA3 binding and is implicated in endocrine resistance. Oncogene 35, 5400–5411 (2016). https://doi.org/10.1038/onc.2016.78
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