BRMS1 appears to regulate osteopontin expression in metastatic breast cancer.

Abstract

3417

The metastasis suppressor gene, BRMS1, suppresses metastasis of multiple metastatic cell lines of human and mouse origin. In order to obtain clues regarding the mechanism of action, expression microarrays were used to compare metastatic cells MDA-MB-435 cells and metastasis-suppressed cells (neo11/435 into which chromosome 11 was introduced and MDA-MB-435/BRMS1 (435BRMS)). Notably, osteopontin (OPN) expression in 435BRMS1 was 5% that of metastatic MDA-MB-435/vector-only cells. The regulation of transcription of OPN by BRMS1 was tested using the OPN promoter tagged to a luciferase reporter. Progressive deletions of the OPN promoter have narrowed the BRMS1-responsive region to -1 to -300 nucleotides. In addition, many pro-apoptotic genes, Bik, Fas/Apo-1, TRAIL, Bid, CRADD were up regulated in metastasis-suppressed cells. While the expression of these pro-apoptotic genes does not indicate ongoing apoptosis, it implies that these cells may be sensitive to apoptosis. To assess this hypothesis 435/BRMS1 and 435/vector-only cells were treated with apoptosis-inducing agents. BRMS1-expressing cells showed increased apoptosis as scored by Annexin V staining. Thus, BRMS1 appears to affect the expression of OPN as well as sensitize cells to apoptosis. [Support: CA87728, DAMD-17-02-1-0541 and NFCR (DRW) and ACS-IRG (LAS)]