BRMS1 Suppresses Breast Cancer Metastasis to Bone via Its Regulation of MicroRNA-125b and Downstream Attenuation of TNF-Alpha and HER2 Signaling Pathways
Revised annual summary 30 Sep 2010-29 Sep 2011
M D ANDERSON CANCER CENTER HOUSTON TX
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BRMS1 is a metastasis suppressor that affects several steps of the metastatic cascade and potently inhibits metastases of many cancer types to various secondary sites. Here we show that BRMS1 has only a marginal effect on expression of HER2 and microRNA-125b. We also failed to detect TNF-alpha in cell lines utilized in this study by several methods. However, we confirmed a strong inverse correlation between expression of HER2 and BRMS1 in human breast cancer specimens. Moreover, we confirmed that cells stably expressing miR-125b exhibit reduced levels of HER2, as compared to vector only cells. In addition, our studies aimed at examining BRMS1 effect on anoikis demonstrate that BRMS1 expressing cells are inherently unable to respond to microenvironmental changes, as they display a significant delay in adhesion to matrix. Mechanistically, these cells in a time-dependent manner exhibit reduced activation of integrins and signaling molecules responsible for focal adhesioncytoskeleton coupling. Lastly, we have preliminary evidence that BRMS1-mediated adhesion changes may be due to a time-dependent inhibition of mesenchymal-to-epithelial transition, which may also play a role in BRMS1 ability to suppress metastatic dissemination. In conclusion, these findings may explain why BRMS1-expressing cells show a greatly decreased survival in circulation in vivo and enhanced anoikis in vitro.
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