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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.To define the in vivo role of SRC-1 in breast cancer, SRC-1/-mice were backcrossed with FVB mice and then crossbred with MMTV-polyoma middle T (PyMT) transgenic mice, 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-/-/PyMTtumors in SRC-1-/-and WT recipient mice revealed that SRC-1 played an intrinsic role in tumor cell metastasis.Furthermore, SRC-1 was upregulated during mammary tumor progression.Disruption of SRC-1 inhibited Ets-2-mediated HER2 expression and PyMT-stimulated Akt activation in the mammary tumors.