title: Metastatic progression with resistance to aromatase inhibitors is driven by the steroid receptor coactivator SRC-1.
abstract: Aromatase inhibitors (AI) are a standard-of-care treatment for postmenopausal, estrogen receptor-positive breast cancers. Although tumor recurrence on AI therapy occurs, the mechanisms underlying acquired resistance to AIs remain unknown. In this study, we examined a cohort of endocrine-treated breast cancer patients and used a cell line model of resistance to the AI letrozole. In patients treated with a first-line AI, hormone receptor switching between primary and resistant tumors was a common feature of disease recurrence. Resistant cells exhibited a switch from steroid-responsive growth to growth factor-responsive and endocrine-independent growth, which was accompanied by the development of a more migratory and disorganized phenotype. Both the resistant cells and tumors from AI-resistant patients showed high expression of the steroid receptor coactivator SRC-1. Direct interactions between SRC-1 and the transcription factor Ets2 regulated Myc and MMP9. SRC-1 was required for the aggressive and motile phenotype of AI-resistant cells. Interestingly, SRC-1 expression in primary and/or recurrent tumors was associated with a reduction in disease-free survival in treated patients. Moreover, there was a significant association between SRC-1 and Ets2 in the recurrent tissue compared with the matched primary tumor. Together, our findings elucidate a mechanism of AI-specific metastatic progression in which interactions between SRC-1 and Ets2 promote dedifferentiation and migration in hormone-dependent breast cancer.
authors: Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors: Jean
authors: J
authors: McBryan
authors: Sarah M
authors: SM
authors: Theissen
authors: Christopher
authors: C
authors: Byrne
authors: Eamon
authors: E
authors: Hughes
authors: Sinead
authors: S
authors: Cocchiglia
authors: Stephen
authors: S
authors: Sande
authors: Jane
authors: J
authors: O'Hara
authors: Paul
authors: P
authors: Tibbitts
authors: Arnold D K
authors: AD
authors: Hill
authors: Leonie S
authors: LS
authors: Young
mesh_terms: D047072:Aromatase Inhibitors / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D045744:Cell Line, Tumor; D018450:Disease Progression; D005260:Female; D006801:Humans; D009362:Neoplasm Metastasis; D056920:Nuclear Receptor Coactivator 1 / Q000378:metabolism*; D013629:Tamoxifen / Q000494:pharmacology*; D014162:Transfection
chemical_list: D047072:Aromatase Inhibitors; D013629:Tamoxifen; D056920:Nuclear Receptor Coactivator 1