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Osteopontin (OPN), a secreted phospho-glycoprotein, has been strongly associated with tumorigenicity and aggressive cancers. Breast cancer metastasis suppressor 1 (BRMS1) expressing (metastasis suppressed) MDA-MB-435 cells expressed significantly lower OPN compared to control, metastatic MDA-MB-435 cells. To investigate the mechanism by which BRMS1 regulates OPN expression, we performed a systematic deletion analysis of OPN promoter using a luciferase reporter system. We have confirmed by gel shift assays and chromatin immunoprecipitations (CHIP) that BRMS1 acts via a novel NFκB site on OPN promoter and represses OPN expression. Our reporter studies also implicate a role for HDAC3 in the BRMS1- mediated suppression of NFκB leading to decreased OPN expression. BRMS1 has been shown to suppress the metastasis of breast cancer and melanoma in animal models. Our results identify OPN as a crucial downstream target of BRMS1. Suppression of OPN may be one of the possible underlying mechanisms of BRMS1-dependent suppression of tumor metastasis. Grant support: The Susan G. Komen Breast Cancer Foundation (BCTR0402317), ACS-IRG (UAB), U.S. Army Medical Research and Materiel Command DAMD-17-02-0541

[Proc Amer Assoc Cancer Res, Volume 47, 2006]