Submitted to: American Association of Cancer Research
Publication Type: Abstract Only
Publication Acceptance Date: 1/25/2011
Publication Date: 4/4/2011
Citation: Khotskaya, Y.B., Beck, B.H., Hurst, D.R., Hung, M., Welch, D.R. 2011. Breast cancer metastasis suppressor 1 (BRMS1) suppresses attachment and spreading of breast cancer cells on 2D and 3D extracellular matrix components by altering focal adhesion-associated signaling [abstract]. American Association of Cancer Research. p.1438. Interpretive Summary:
Technical Abstract: Metastatic dissemination of cancer cells from primary tumor to secondary sites is a multi-step process that depends heavily on the ability of cancer cells to respond to the microenvironmental cues, such as changes in composition of surrounding extracellular matrix (ECM), by adapting their adhesion abilities and undergoing cytoskeletal rearrangement. Many of these interactions between cancer cells and ECM are mediated by signaling cascades initiated at the cell surface through activation of integrins and growth factor receptors. BRMS1, or Breast cancer Metastasis Suppressor 1, belongs to a family of metastasis suppressor genes and has been shown to affect several steps of the metastatic cascade. BRMS1-expressing cells shed by the primary tumor can enter the circulation and reach secondary sites, where they remain largely as single cells. Moreover, ectopic expression of BRMS1 results in a significant decrease in survival of tumor cells within blood stream, increased susceptibility to anoikis and inability to form colonies at secondary organ sites, all events that could be attributed to failure of BRMS1 expressing cells to activate integrins and strongly adhere to ECM components. Here, we show that BRMS1 expression in MDA-MB-231 and MDA-MB-435 cells did not significantly alter expression levels of the integrin monomers tested. However, after short-term (15-30 minutes) plating of cells onto mixed ECM or individual ECM components (collagen I, collagen IV, or fibronectin) under 2D conditions, BRMS1-expressing cells exhibited reduced activation of beta 1 integrin, focal adhesion kinase (FAK), and scaffolding protein Talin1, as well as a decrease in their localization to focal adhesions. Furthermore, short-term plating of BRMS1-expressing cells on collagens I or IV or fibronectin resulted in marked inhibition of cytoskeletal rearrangement and failure to form cellular adhesion projections, as compared to cells vector-transfected cells. In addition, under 3D conditions, BRMS1-expressing cells remained rounded and failed to reorganize their cytoskeleton even after 24-hour stimulation with serum. Taken together, we believe that these findings demonstrate that BRMS1-expressing breast cancer cells are inherently unable to respond to microenvironment changes, which may explain why they exhibit reduced survival in circulation, increased susceptibility to anoikis, and decreased colonization of secondary sites.