RT Journal Article
SR Electronic
T1 Metastatic Progression with Resistance to Aromatase Inhibitors Is Driven by the Steroid Receptor Coactivator SRC-1
JF Cancer Research
JO Cancer Res
FD American Association for Cancer Research
SP 548
OP 559
DO 10.1158/0008-5472.CAN-11-2073
VO 72
IS 2
A1 McBryan, Jean
A1 Theissen, Sarah M.
A1 Byrne, Christopher
A1 Hughes, Eamon
A1 Cocchiglia, Sinead
A1 Sande, Stephen
A1 O'Hara, Jane
A1 Tibbitts, Paul
A1 Hill, Arnold D.K.
A1 Young, Leonie S.
YR 2012
UL http://cancerres.aacrjournals.org/content/72/2/548.abstract
AB 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. Cancer Res; 72(2); 548–59. ©2011 AACR.