title: An epigenomic approach to therapy for tamoxifen-resistant breast cancer.
abstract: Tamoxifen has been a frontline treatment for estrogen receptor alpha (ERα)-positive breast tumors in premenopausal women. However, resistance to tamoxifen occurs in many patients. ER still plays a critical role in the growth of breast cancer cells with acquired tamoxifen resistance, suggesting that ERα remains a valid target for treatment of tamoxifen-resistant (Tam-R) breast cancer. In an effort to identify novel regulators of ERα signaling, through a small-scale siRNA screen against histone methyl modifiers, we found WHSC1, a histone H3K36 methyltransferase, as a positive regulator of ERα signaling in breast cancer cells. We demonstrated that WHSC1 is recruited to the ERα gene by the BET protein BRD3/4, and facilitates ERα gene expression. The small-molecule BET protein inhibitor JQ1 potently suppressed the classic ERα signaling pathway and the growth of Tam-R breast cancer cells in culture. Using a Tam-R breast cancer xenograft mouse model, we demonstrated in vivo anti-breast cancer activity by JQ1 and a strong long-lasting effect of combination therapy with JQ1 and the ER degrader fulvestrant. Taken together, we provide evidence that the epigenomic proteins BRD3/4 and WHSC1 are essential regulators of estrogen receptor signaling and are novel therapeutic targets for treatment of Tam-R breast cancer.
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Qin
authors.initials: Q
authors.lastname: Feng
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Shea
authors.affiliation: Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Chad J
authors.initials: CJ
authors.lastname: Creighton
authors.affiliation: Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Cristian
authors.initials: C
authors.lastname: Coarfa
authors.affiliation: Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Susan G
authors.initials: SG
authors.lastname: Hilsenbeck
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Rainer
authors.initials: R
authors.lastname: Lanz
authors.affiliation: 1] Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA [2] Department of Medicine-Hematology & Oncology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: He
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: 1] Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA [2] Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA [3] Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Xiaoyong
authors.initials: X
authors.lastname: Fu
authors.affiliation: 1] Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA [2] Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA [3] Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Agostina
authors.initials: A
authors.lastname: Nardone
authors.affiliation: Department of Pharmacology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Yongcheng
authors.initials: Y
authors.lastname: Song
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: James
authors.initials: J
authors.lastname: Bradner
authors.affiliation: 1] Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA [2] Department of Medicine-Hematology & Oncology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Mitsiades
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Constantine S
authors.initials: CS
authors.lastname: Mitsiades
authors.affiliation: 1] Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA [2] Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA [3] Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: C Kent
authors.initials: CK
authors.lastname: Osborne
authors.affiliation: 1] Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA [2] Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA [3] Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Schiff
authors.affiliation: 1] Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA [2] Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Bert W
authors.initials: BW
authors.lastname: O'Malley
mesh_terms: D000818:Animals; D001381:Azepines / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D057890:Epigenomics; D004958:Estradiol / Q000031:analogs & derivatives / Q000627:therapeutic use; D047628:Estrogen Receptor alpha / Q000096:biosynthesis / Q000502:physiology*; D005260:Female; D000077267:Fulvestrant; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000502:physiology; D016601:RNA-Binding Proteins / Q000502:physiology; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013629:Tamoxifen / Q000494:pharmacology / Q000627:therapeutic use*; D014157:Transcription Factors / Q000502:physiology; D014230:Triazoles / Q000627:therapeutic use; D000092468:Bromodomain Containing Proteins
chemical_list: D001381:Azepines; D018797:Cell Cycle Proteins; D004958:Estradiol; D047628:Estrogen Receptor alpha; D000077267:Fulvestrant; D011495:Histone-Lysine N-Methyltransferase; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; D013629:Tamoxifen; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C109106:BRD3 protein, human; D000092468:Bromodomain Containing Proteins; C441289:BRD4 protein, human; C506487:ESR1 protein, human; C419586:NSD2 protein, human