Disruption of the SRC-1 gene in mice suppresses breast cancer metastasis without affecting primary tumor formation.
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.
Wang
Shu
S
Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Yuan
Yuhui
Y
Liao
Lan
L
Kuang
Shao-Qing
SQ
Tien
Jean Ching-Yi
JC
O'Malley
Bert W
BW
Xu
Jianming
J
D000818:Animals; D001943:Breast Neoplasms / Q000209:etiology / Q000235:genetics / Q000473:pathology*; D002454:Cell Differentiation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D051548:Histone Acetyltransferases / Q000235:genetics*; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology*; D009368:Neoplasm Transplantation; D056920:Nuclear Receptor Coactivator 1; D050787:Proto-Oncogene Protein c-ets-2 / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*
D051548:Histone Acetyltransferases; D016173:Macrophage Colony-Stimulating Factor; D056920:Nuclear Receptor Coactivator 1; D050787:Proto-Oncogene Protein c-ets-2; D018719:Erb-b2 Receptor Tyrosine Kinases; D014157:Transcription Factors; C538861:Ncoa1 protein, mouse; C524056:Erbb2 protein, mouse