title: Global characterization of the SRC-1 transcriptome identifies ADAM22 as an ER-independent mediator of endocrine-resistant breast cancer.
abstract: The development of breast cancer resistance to endocrine therapy results from an increase in cellular plasticity that permits the emergence of a hormone-independent tumor. The steroid coactivator protein SRC-1, through interactions with developmental proteins and other nonsteroidal transcription factors, drives this tumor adaptability. In this discovery study, we identified ADAM22, a non-protease member of the ADAM family of disintegrins, as a direct estrogen receptor (ER)-independent target of SRC-1. We confirmed SRC-1 as a regulator of ADAM22 by molecular, cellular, and in vivo studies. ADAM22 functioned in cellular migration and differentiation, and its levels were increased in endocrine resistant-tumors compared with endocrine-sensitive tumors in mouse xenograft models of human breast cancer. Clinically, ADAM22 was found to serve as an independent predictor of poor disease-free survival. Taken together, our findings suggest that SRC-1 switches steroid-responsive tumors to a steroid-resistant state in which the SRC-1 target gene ADAM22 has a critical role, suggesting this molecule as a prognostic and therapeutic drug target that could help improve the treatment of endocrine-resistant breast cancer.
authors.affiliation: Endocrine Oncology Research, Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Damian
authors.initials: D
authors.lastname: McCartan
authors.forename: Jarlath C
authors.initials: JC
authors.lastname: Bolger
authors.forename: Aílis
authors.initials: A
authors.lastname: Fagan
authors.forename: Christopher
authors.initials: C
authors.lastname: Byrne
authors.forename: Yuan
authors.initials: Y
authors.lastname: Hao
authors.forename: Li
authors.initials: L
authors.lastname: Qin
authors.forename: Marie
authors.initials: M
authors.lastname: McIlroy
authors.forename: Jianming
authors.initials: J
authors.lastname: Xu
authors.forename: Arnold D
authors.initials: AD
authors.lastname: Hill
authors.forename: Peadar Ó
authors.initials: PÓ
authors.lastname: Gaora
authors.forename: Leonie S
authors.initials: LS
authors.lastname: Young
mesh_terms: D051722:ADAM Proteins / Q000502:physiology*; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009419:Nerve Tissue Proteins / Q000502:physiology*; D056920:Nuclear Receptor Coactivator 1 / Q000235:genetics*; D011960:Receptors, Estrogen / Q000378:metabolism*; D059467:Transcriptome
chemical_list: D018931:Antineoplastic Agents, Hormonal; D009419:Nerve Tissue Proteins; D011960:Receptors, Estrogen; D056920:Nuclear Receptor Coactivator 1; D051722:ADAM Proteins; C498474:ADAM22 protein, human
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