Carcinogenesis Advance Access originally published online on May 25, 2005
Carcinogenesis 2005 26(10):1706-1715; doi:10.1093/carcin/bgi137
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Carcinogenesis vol.26 no.10 © Oxford University Press 2005; all rights reserved.
The p160 family coactivators regulate breast cancer cell proliferation and invasion through autocrine/paracrine activity of SDF-1
/CXCL12
1 Department of Surgery, 2 Walther Oncology Center and 3 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA, 4 Walther Cancer Institute, North Meridian Street Indianapolis, IN 46208, USA and 5 Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20007, USA
* To whom correspondence should be addressed at: R4-202, Indiana Cancer Institute, 1044 West Walnut Street, Indianapolis, IN 46202, USA. Tel: +1 317 278 2238; Fax: +1 317 274 0396; Email: hnakshat{at}iupui.edu
Estrogen receptors (ERs) regulate the transcription of genes involved in breast cancer cell proliferation, invasion and metastasis. In addition to ligand concentration, phosphorylation and coactivator/corepressor levels control ER-dependent transcription. In this study, we used MCF-7 breast cancer sublines with variable levels of the steroid receptor coactivator 1 (SRC-1) to investigate the importance of coactivator levels in basal and estrogen-inducible expression of SDF-1
/CXCL12, cathepsin D and cMyc. Basal expression of SDF-1 and cMyc but not of cathepsin D was substantially lower in a MCF-7 subline lacking SRC-1 ((MCF-7/p2) compared with MCF-7 sublines expressing SRC-1 (MCF-7/p1 and LCC2). Although estrogen efficiently induced SDF-1 in MCF-7/p1 cells, very little induction of this gene was observed in MCF-7/p2 cells. The absence of SRC-1 had no effect on estrogen-inducible expression cMyc and cathepsin D suggesting that coactivator levels determine the expression of only a subset of estrogen-regulated genes. Introduction of SRC-1, SRC-2/TIF-2 or SRC-3/AIB1 increased basal expression of SDF-1 in MCF-7/p2 cells. Consistent with the role of SDF-1 in mediating estrogen-induced proliferation, estrogen failed to increase proliferation of MCF-7/p2 cells. In matrigel invasion assays, conditioned media from MCF-7/p1 but not MCF-7/p2 cells increased invasion of cancer cells expressing metastasis-associated genes and CXCR4, the receptor for SDF-1. These results suggest that coactivators control SDF-1 expression, which mediates estrogen-induced proliferation and invasion through autocrine and paracrine mechanisms, respectively. These results also provide a molecular explanation for recent observations linking co-overexpression of coactivators and her2/neu with poor prognosis: coactivators increase SDF-1 expression whereas her2/neu stabilize CXCR4 protein.
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