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

Proc Natl Acad Sci U S A. 2009 Jan 6;106(1):151-6. doi: 10.1073/pnas.0808703105. Epub 2008 Dec 24.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / etiology
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology*
  • Cell Differentiation
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Histone Acetyltransferases / genetics*
  • Macrophage Colony-Stimulating Factor / genetics
  • Mice
  • Mice, Knockout
  • Neoplasm Metastasis / genetics
  • Neoplasm Metastasis / pathology*
  • Neoplasm Transplantation
  • Nuclear Receptor Coactivator 1
  • Proto-Oncogene Protein c-ets-2 / genetics
  • Receptor, ErbB-2 / genetics
  • Transcription Factors / genetics*

Substances

  • Proto-Oncogene Protein c-ets-2
  • Transcription Factors
  • Macrophage Colony-Stimulating Factor
  • Histone Acetyltransferases
  • Ncoa1 protein, mouse
  • Nuclear Receptor Coactivator 1
  • Erbb2 protein, mouse
  • Receptor, ErbB-2