Disruption of the <i>SRC-1</i> gene in mice suppresses breast cancer metastasis without affecting primary tumor formation

Abstract

Steroid receptor coactivator-1 (SRC-1) is a coactivator for nuclear hormone receptors such as estrogen and progesterone receptors and certain other transcription factors such as Ets-2 and PEA3. SRC-1 expression in breast cancer is associated with HER2 and c-Myc expression and with reduced disease-free survival. In this study, SRC-1(-/-) mice were backcrossed with FVB mice and then cross-bred with MMTV-polyoma middle T antigen (PyMT) mice to investigate the role of SRC-1 in breast cancer. Although mammary tumor initiation and growth were similar in SRC-1(-/-)/PyMT and wild-type (WT)/PyMT mice, genetic ablation of SRC-1 antagonized PyMT-induced restriction of mammary ductal differentiation and elongation. SRC-1(-/-)/PyMT mammary tumors were also more differentiated than WT/PyMT mammary tumors. The intravasation of mammary tumor cells and the frequency and extent of lung metastasis were drastically reduced in SRC-1(-/-)/PyMT mice compared with WT/PyMT mice. Metastatic analysis of transplanted WT/PyMT and SRC-1(-/-)/PyMT tumors in SRC-1(-/-) and WT recipient mice revealed that SRC-1 played an intrinsic role in tumor cell metastasis. Furthermore, SRC-1 was up-regulated during mammary tumor progression. Disruption of SRC-1 inhibited Ets-2-mediated HER2 expression and PyMT-stimulated Akt activation in the mammary tumors. Disruption of SRC-1 also suppressed colony-stimulating factor-1 (CSF-1) expression and reduced macrophage recruitment to the tumor site. These results suggest that SRC-1 specifically promotes metastasis without affecting primary tumor growth. SRC-1 may promote metastasis through mediating Ets-2-mediated HER2 expression and activating CSF-1 expression for macrophage recruitment. Therefore, functional interventions for coactivators like SRC-1 may provide unique approaches to control breast cancer progression and metastasis.