PMID- 27041579 OWN - NLM STAT- MEDLINE DCOM- 20170829 LR - 20210816 IS - 1476-5594 (Electronic) IS - 0950-9232 (Print) IS - 0950-9232 (Linking) VI - 35 IP - 41 DP - 2016 Oct 13 TI - FOXC1 is involved in ERalpha silencing by counteracting GATA3 binding and is implicated in endocrine resistance. PG - 5400-5411 LID - 10.1038/onc.2016.78 [doi] AB - Estrogen receptor-alpha (ERalpha) 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 ERalpha signaling in breast cancer. However, previous studies of ERalpha regulation have focused on luminal and HER2-positive subtypes rather than basal-like breast cancer (BLBC), in which ERalpha 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 ERalpha 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 ERalpha gene and thereby downregulates ERalpha 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 ERalpha promoter region, overexpression of FOXC1 hinders recruitment of RNA polymerase II and increases histone H3K9 trimethylation at ERalpha 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 ERalpha expression in BLBC. This study suggests a new paradigm to study ERalpha regulation during breast cancer progression and indicates a role of FOXC1 in the modulation of cellular response to endocrine treatment. FAU - Yu-Rice, Y AU - Yu-Rice Y AD - Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA. FAU - Jin, Y AU - Jin Y AD - Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA. FAU - Han, B AU - Han B AD - Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA. FAU - Qu, Y AU - Qu Y AD - Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA. FAU - Johnson, J AU - Johnson J AD - Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA. FAU - Watanabe, T AU - Watanabe T AD - Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA. FAU - Cheng, L AU - Cheng L AD - Department of Breast and Thyroid Surgery, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China. FAU - Deng, N AU - Deng N AD - Department of Surgery, Biostatistics and Bioinformatics Research Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA. FAU - Tanaka, H AU - Tanaka H AD - Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA. FAU - Gao, B AU - Gao B AD - Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA. FAU - Liu, Z AU - Liu Z AD - Department of Surgery, Biostatistics and Bioinformatics Research Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA. FAU - Sun, Z AU - Sun Z AD - Department of Breast and Thyroid Surgery, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China. FAU - Bose, S AU - Bose S AD - Department of Pathology, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA. FAU - Giuliano, A E AU - Giuliano AE AD - Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA. FAU - Cui, X AU - Cui X AD - Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA. LA - eng GR - R01 CA151610/CA/NCI NIH HHS/United States PT - Journal Article DEP - 20160404 PL - England TA - Oncogene JT - Oncogene JID - 8711562 RN - 0 (Antineoplastic Agents, Hormonal) RN - 0 (ESR1 protein, human) RN - 0 (Estrogen Receptor alpha) RN - 0 (FOXC1 protein, human) RN - 0 (Forkhead Transcription Factors) RN - 0 (GATA3 Transcription Factor) RN - 0 (GATA3 protein, human) RN - 094ZI81Y45 (Tamoxifen) SB - IM MH - Antineoplastic Agents, Hormonal/administration & dosage MH - Breast Neoplasms/drug therapy/*genetics/pathology MH - Carcinogenesis/*genetics MH - Drug Resistance, Neoplasm/drug effects/genetics MH - Estrogen Receptor alpha/biosynthesis/*genetics MH - Female MH - Forkhead Transcription Factors/*genetics/metabolism MH - GATA3 Transcription Factor/*genetics/metabolism MH - Gene Expression Regulation, Neoplastic MH - Humans MH - MCF-7 Cells MH - Neoplasm Recurrence, Local/genetics/pathology MH - Protein Binding MH - Tamoxifen/administration & dosage PMC - PMC5287293 MID - NIHMS760172 COIS- Xiaojiang Cui is a named inventor for patent applications regarding the role of FOXC1 in cancer. The other authors declare no conflict of interest. EDAT- 2016/04/05 06:00 MHDA- 2017/08/30 06:00 PMCR- 2017/02/02 CRDT- 2016/04/05 06:00 PHST- 2015/09/11 00:00 [received] PHST- 2016/01/05 00:00 [revised] PHST- 2016/02/12 00:00 [accepted] PHST- 2016/04/05 06:00 [pubmed] PHST- 2017/08/30 06:00 [medline] PHST- 2016/04/05 06:00 [entrez] PHST- 2017/02/02 00:00 [pmc-release] AID - onc201678 [pii] AID - 10.1038/onc.2016.78 [doi] PST - ppublish SO - Oncogene. 2016 Oct 13;35(41):5400-5411. doi: 10.1038/onc.2016.78. Epub 2016 Apr 4.