title: FOXC1 is involved in ERα silencing by counteracting GATA3 binding and is implicated in endocrine resistance.
abstract: 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.
authors.affiliation: Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Yu-Rice
authors.affiliation: Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Han
authors.affiliation: Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Qu
authors.affiliation: Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Johnson
authors.affiliation: Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Department of Breast and Thyroid Surgery, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: L
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Department of Surgery, Biostatistics and Bioinformatics Research Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: N
authors.initials: N
authors.lastname: Deng
authors.affiliation: Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Gao
authors.affiliation: Department of Surgery, Biostatistics and Bioinformatics Research Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Breast and Thyroid Surgery, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Department of Pathology, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Bose
authors.affiliation: Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: A E
authors.initials: AE
authors.lastname: Giuliano
authors.affiliation: Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: X
authors.initials: X
authors.lastname: Cui
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D047628:Estrogen Receptor alpha / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D050990:GATA3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000473:pathology; D011485:Protein Binding; D013629:Tamoxifen / Q000008:administration & dosage
chemical_list: D018931:Antineoplastic Agents, Hormonal; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C112743:FOXC1 protein, human; D051858:Forkhead Transcription Factors; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D013629:Tamoxifen