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FOXC1 Is Involved in ERΑ Silencing by Counteracting GATA3

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FOXC1 Is Involved in ERΑ Silencing by Counteracting GATA3 Oncogene (2016) 35, 5400–5411 © 2016 Macmillan Publishers Limited, part of Springer Nature. All rights reserved 0950-9232/16 www.nature.com/onc ORIGINAL ARTICLE FOXC1 is involved in ERα silencing by counteracting GATA3 binding and is implicated in endocrine resistance Y Yu-Rice1, Y Jin1, B Han1,YQu1, J Johnson1, T Watanabe1, L Cheng2, N Deng3, H Tanaka1, B Gao1, Z Liu3, Z Sun2, S Bose4, AE Giuliano1 and X Cui1 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. Oncogene (2016) 35, 5400–5411; doi:10.1038/onc.2016.78; published online 4 April 2016 INTRODUCTION mechanisms restricting ERα expression in BLBC. In addition, up to Breast cancer can be classified into four major molecular subtypes ~ 30% of ER-positive breast tumors have been reported to recur including luminal A, luminal B, HER2-positive and basal-like breast with an ER-negative phenotype after endocrine therapy.11 It is not cancer (BLBC) based on different gene expression signatures.1 clear what causes the diminished ERα expression and endocrine The luminal subtype is characterized by estrogen receptor therapy resistance.11 Unraveling the mechanism inhibiting ERα expression (ER-positive), whereas BLBC often has a triple- will provide a new insight into the molecular basis of ERα-negative negative phenotype (ER-negative/progesterone receptor-nega- breast cancer and a possible explanation for ERα status changes 2 tive/HER2-negative). Notably, the molecular subtypes display during antiestrogen treatment. highly significant differences in the choices of treatment strategies FOXC1, a member of the forkhead box (FOX) transcription factor 3 and prediction of recurrence, metastasis and survival. Luminal superfamily, has important roles in the development of the brain, breast cancer is usually associated with a less-aggressive cancer heart and eye during the embryogenesis.12 A recent study phenotype and more favorable prognostic outcome compared to 3 demonstrated FOXC1 as a pivotal diagnostic marker for patients with BLBC. Estrogen signaling is a target for endocrine BLBC.13,14 In addition to BLBC, FOXC1 is associated with other α therapy, and greater ER expression correlates with a better types of cancers including hepatocellular carcinoma,15 gastric response to endocrine therapy, including tamoxifen.4 In contrast, cancer16 and non-small cell lung cancer.17 FOXC1 stimulates the only option at present for systemic therapy of BLBC is 14 5 human cancer cell proliferation, migration and invasion. chemotherapy due to the lack of targetable markers. α A number of studies have addressed the regulatory mechan- As opposed to ER , the expression of FOXC1 is low or absent in 14 α isms of estrogen signaling in breast cancer. Pioneer factor FOXA1,6 luminal breast cancer cells. The fact that FOXC1 and ER are GATA-binding protein 3 (GATA3),7 coactivators and corepressors,8 highly associated with two different breast cancer subtypes and epigenetic modifications such as promoter hypermethylation9 and their expressions are mutually exclusive has prompted us to ERα ubiquitination10 have been identified as regulators of ERα postulate negative regulation between the two transcription expression and transcriptional activity. Although previous work factors. In this study, we characterize the effect of FOXC1 on ERα has greatly advanced our understanding of the function and expression in breast cancer cells and explore the possible regulation of ERα in luminal breast cancer, less is known about the mechanism of this inhibition. It offers new mechanistic insight 1Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA; 2Department of Breast and Thyroid Surgery, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China; 3Department of Surgery, Biostatistics and Bioinformatics Research Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA and 4Department of Pathology, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Correspondence: Dr X Cui, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Davis Building 2065, Los Angeles, CA 90048, USA. E-mail: [email protected] Received 11 September 2015; revised 5 January 2016; accepted 12 February 2016; published online 4 April 2016 FOXC1 suppresses ERα in breast cancer Y Yu-Rice et al 5401 into FOXC1-relavant endocrine resistance and ER-positive breast FOXC1 prevents GATA3 binding to the same regulatory regions cancer recurrence. upstream of the ERα gene FOXC1 is known to bind to a nine-base-pair core sequence 5′-GTAAA(T/C)A(A/T/C)(A/T/G)-3′.31 Based on the consensus RESULTS sequence, we found three putative FOXC1-binding sites located α FOXC1 downregulates ERα expression and its transcriptional at enhancer 1 and promoters B and C upstream of the ER gene α activity (Figure 2a). The genomic organization of human ER gene regulatory region was illustrated based on previous studies.7,32 We first confirmed the inverse correlation of ERα and FOXC1 in FOXC1 in vivo binding to the three sites was validated by ChIP- breast cancer tissues using expression data from The Cancer qPCR analysis of the immunoprecipitated DNA in MCF-7 cells. As Genome Atlas provisional data sets at cBioPortal (www.cbioportal. expected, overexpression of FOXC1 considerably enhanced the org) (Supplementary Figure S1a) and breast cancer cell lines recruitment of FOXC1 to all three sites in the regulatory regions of (Supplementary Figure S1b and S1c). Then we sought to ERα compared with control (Figure 2b, left). We then speculated α determine whether FOXC1 regulates ER expression. Quantitative that these direct FOXC1-DNA interactions interfere with the reverse transcriptase–PCR (qRT–PCR) results suggested that over- accessibility of transcription factors or coregulators that conse- expression of FOXC1 in three common luminal breast cancer quently leads to the inhibition of ERα expression. GATA3, a well- cell lines led to reduced mRNA expression of ERα (ESR1), but not studied transcription factor with a DNA consensus binding ERβ (ESR2) (Figure 1a). In agreement with these results, protein sequence 5′-(A/T)GATA(A/G)-3′, positively regulates expression of levels of ERα and progesterone receptor, a well-established ERα.7 We have also verified that GATA3 is a positive regulator of estrogen-regulated gene,18 were decreased by FOXC1 over- ERα mRNA and protein expression in the MCF-7 cells used in this expression in those luminal breast cancer cell lines (Figure 1b study (Supplementary Figure S2a). In reference to the previous and Supplementary Figure S1d). reports7,33 and the consensus DNA-binding sequences of the well- We then assessed the effect of FOXC1 overexpression on ERα known ERα regulators, we identified GATA3-binding sites in transcriptional activity. According to the result of estrogen proximity to or overlapping with the three above experimentally response element (ERE)-luciferase reporter assays, reduced ERE- confirmed FOXC1 sites (Figure 2a). Prior to examining the possible luciferase signals were detected in the FOXC1-overexpressing binding competition between GATA3 and FOXC1, we system- MCF-7 and T47D cells relative to vector control (Figure 1c). atically assessed GATA3 expression in relation to FOXC1. FOXC1 Chromatin immunoprecipitation (ChIP) assays followed by qPCR overexpression decreased the GATA3 mRNA and protein expres- analysis were further performed to determine whether the sion in MCF-7 cells, whereas FOXC1 overexpression exerted no reduced luciferase signaling is due to the decreased binding effect on GATA3 expression in T47D and ZR-75 cells (Supplementary Figure S2b). The mRNA expression levels of between ERα and EREs. Three well-known ERα-regulated genes GATA3 and FOXC1 are inversely correlated according to The including growth regulation by estrogen
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