P5-12-01: Aromatase Inhibitor Specific Metastasis Is Driven by the Steroid Receptor Coactivator SRC-1.

Abstract

Abstract Aromatase Inhibitors are currently one of the most promising therapies of estrogen-receptor positive breast cancer in postmenopausal women. Even though many women initially respond to the treatment, approximately 30–40% will acquire resistance and relapse within 5 years. The mechanisms involved in the development of resistance to AIs however are poorly understood as long term follow up is only now becoming available. To investigate the mechanisms involved in AI-specific tumour recurrence, we generated a cell line resistant to the AI Letrozole (LetR) and examined a cohort of endocrine treated breast cancer patients (n=150). In patients treated with a first-line AI (n=89), we found that hormone receptor switching between the primary tumour and the resistant metastasis was a common feature of disease recurrence. More so, this switch accompanied the development of a phenotype displaying an increase in migratory capacity and loss of organisation. Both the resistant cell model and AI resistant tumour samples expressed high levels of the steroid receptor coactivator SRC-1. We also found that the interaction between SRC-1 and the transcription factor Ets2 was involved in the regulation of Myc and MMP9 expression and that SRC-1 was required for the aggressive AI resistant phenotype. Expression of SRC-1 in the primary and/or recurrent tumour associated with poor disease free survival (p=0.01, n=89) in the AI treated population. A significant coassociation between SRC-1 and Ets2 in the nucleus of the recurrent tissue compared with the matched primary tumour was also observed (p=0.0004, n=3). These data describe a novel signaling mechanism of AI-specific metastatic progression where SRC-1 utilizes Ets2 to promote de-differentiation and migration to drive disease progression. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-12-01.