Submitted to: Molecular Carcinogenesis
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/17/2013
Publication Date: 9/2/2013
Citation: Khotskaya, Y.B., Beck, B.H., Hurst, D.R., Han, Z., Xia, W., Hung, M., Welch, D.R. 2013. Expression of metastasis suppressor BRMS1 in breast cancer cells results in a marked delay in cellular adhesion to matrix. Molecular Carcinogenesis. 53(12):1011-1026. Interpretive Summary: Metastasis is the process by which tumor cells spread to distant sites within the body. In breast cancer patients, poor survival is closely linked to the spreading of breast cancer cells to distant organs such as the lungs. Therapies designed to stop the process of metastasis, or the effective treatment of cells that have already disseminated, are desperately needed. In the present study, we investigated a gene called breast cancer metastasis suppressor 1 (BRMS1), which has been previously shown to suppress the development of lung metastases in mouse models of breast cancer. Despite the obvious potential of BRMS1 as an anti-metastatic, little is known about the mechanisms of its action. In this study we found that cells artificially engineered to express BRMS1 can adhere to multiple substrates (designed to mimic tissues within the body), but not firmly like control tumor cells. Also, unlike control tumor cells plated on different substrate, BRMS1-expressing cells were rounded and failed to form invasive colonies. These results enhance our understanding on how BRMS1 may inhibit metastasis, and could lead to improved therapies for patients suffering from metastatic breast cancer.
Technical Abstract: Metastatic dissemination is a multi-step process that depends on cancer cells’ ability to respond to microenvironmental cues by adapting adhesion abilities and undergoing cytoskeletal rearrangement. Breast Cancer Metastasis Suppressor 1 (BRMS1) affects several steps of the metastatic cascade: it decreases survival in circulation, increases susceptibility to anoikis, and reduces capacity to colonize secondary organs. In this report, BRMS1 expression is shown to not significantly alter expression levels of integrin monomers, while time-lapse and confocal microscopy revealed that BRMS1-expressing cells exhibited reduced activation of both ß1 integrin and focal adhesion kinase, and decreased localization of these molecules to sites of focal adhesions. Short-term plating of BRMS1-expressing cells onto collagen or fibronectin markedly decreased cytoskeletal reorganization and formation of cellular adhesion projections. Under 3D culture conditions, BRMS1-expressing cells remained rounded and failed to reorganize their cytoskeleton and form invasive colonies. Taken together, BRMS1-expressing breast cancer cells are greatly attenuated in their ability to respond to microenvironment changes. These data identify BRMS1 as a potential biomarker able of predicting patient prognosis, but only when assayed on cells that completed first steps of metastasis.