Abstract 5114: SRC-1 Up-regulates Integrin α5 Expression and Enhances Breast Cancer Metastasis

Abstract

Abstract Steroid receptor coactivator-1 (SRC-1) is a member of the p160 SRC family, which also contains SRC-2 (TIF2/GRIP1) and SRC-3 (AIB1, p/CIP, ACTR, RAC3, TRAM-1). These molecules can interact with nuclear hormone receptors and certain other transcription factors to promote gene expression. In breast cancer, SRC-1 expression positively correlates with HER2 expression, disease recurrence and resistance to endocrine therapy. Our previous work has demonstrated that genetic ablation of SRC-1 in mice significantly suppresses breast cancer metastasis without affecting primary tumor initiation and growth in the MMTV-PyMT (polyoma middle T) mouse model. However, the mechanisms by which SRC-1 promotes breast cancer metastasis are unclear. To address the role of SRC-1 overexpression in breast cancer metastasis and mechanism, we generated MMTV-hSRC1 transgenic mice and found that MMTV-hSRC1 virgin mice exhibited normal mammary gland development. To take an advantage of the avian virus-mediated oncogene expression system, we crossed MMTV-hSRC1 mice to MMTV-tva mice and generated MMTV-hSRC1;MMTV-tva bi-transgenic mice. Intraductal injection of RCAS-PyMT avian viruses induced more metastasis in these bi-transgenic mice than in MMTV-tva mono-transgenic mice, suggesting that SRC-1 overexpression promotes lung metastasis. We also performed studies using MMTV-PyMT;SRC1−/− (KO) and MMTV-PyMT;SRC1+/+ (WT) cell lines derived from primary mouse mammary tumors. KO cells showed much lower migration and invasion capabilities than WT cells. KO cells also adhered much slowly to fibronectin and had reduced levels of active FAK, c-Src and Rac1. Mechanistic analyses revealed that SRC-1 was associated with a promoter region of integrin α5 with C/EBP and AP-1 binding sites and the integrin α5 gene might be a direct target of SRC-1. Accordingly, knockdown of integrin α5 in WT cells reduced cell adhesion and migration. Therefore, one of the pathways for SRC-1 to promote breast cancer cell migration and metastasis is to up-regulate integrin α5, leading to super activation of FAK, c-Src and Rac1. Our study provides a possibility to inhibit SRC-1-promoted breast cancer metastasis by targeting the integrin α5 function. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5114.