|COOK, LEAH - University Of Alabama
|COA, XUEMEI - University Of Alabama
|DOWELL, ALEXANDER - University Of Alabama
|DEBIES, MICHAEL - University Of Alabama
|EDMONDS, MICK - University Of Alabama
|KESTERSON, ROBERT - University Of Alabama
|DESMOND, RENEE - University Of Alabama
|FROST, ANDRA - University Of Alabama
|HURST, DOUGLAS - University Of Alabama
|WELCH, DANNY - University Of Alabama
Submitted to: Clinical and Experimental Metastasis
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/2/2012
Publication Date: 1/13/2012
Citation: Cook, L., Coa, X., Dowell, A.E., Debies, M.T., Edmonds, M.D., Beck, B.H., Kesterson, R.A., Desmond, R.A., Frost, A.R., Hurst, D.R., Welch, D.R. 2012. Ubiquitous Brms1 expression is critical for mammary carcinoma metastasis suppression via promotion of apoptosis. Clinical and Experimental Metastasis. 29:315–325.
Interpretive Summary: In breast cancer patients, poor survival is closely linked to the spreading of breast cancer cells to distant organs such as the lungs (a process termed metastasis). Effective treatment of these disseminated tumor cells is limited and new therapies 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. However, the majority of previous studies on Brms1 have artificially engineered breast cancer cells to express Brms1 and then injected these cells into healthy mice. While informative, these experimental protocols do not fully model the early events of tumor development including: malignant transformation, tumor initiation, tumor progression, and the host-tumor interactions that occur throughout tumor development. Here we developed a mouse model where Brms1 was expressed in all tissues (called ubiquitous expression) of the mouse. These transgenic mice were then selectively bred with a mouse strain called polyoma middle T, which are mice that reliably develop mammary tumors that arise and spontaneously metastasize in a manner very similar to the human disease. By studying their offspring, we found that ubiquitous Brms1 expression protected against mammary tumor cell metastasis. This study provides new insight into mechanisms of metastasis suppression by Brms1 and could lead to improved therapies for patients suffering from metastatic breast cancer.
Technical Abstract: Morbidity and mortality of breast cancer patients are drastically increased when primary tumor cells are able to spread to distant sites and proliferate to become secondary lesions. Effective treatment of metastatic disease has been limited; therefore, an increased molecular understanding to identify biomarkers and therapeutic targets is needed. Breast cancer metastasis suppressor 1 (BRMS1) suppresses development of pulmonary metastases when expressed in a variety of cancer types, including metastatic mammary carcinoma. Little is known of Brms1 function throughout the initiation and progression of mammary carcinoma. The goal of this study was to investigate mechanisms of Brms1-mediated metastasis suppression in transgenic mice that express Brms1 using polyoma middle T oncogene-induced models. Brms1 expression did not significantly alter growth of the primary tumors. When expressed ubiquitously using a b-actin promoter, Brms1 suppressed pulmonary metastasis and promoted apoptosis of tumor cells located in the lungs but not in the mammary glands. Surprisingly, selective expression of Brms1 in the mammary gland using the MMTV promoter did not significantly block metastasis nor did it promote apoptosis in the mammary glands or lung, despite MMTV-induced expression within the lungs. These results strongly suggest that cell type-specific over-expression of Brms1 is important for Brms1-mediated metastasis suppression.