All ETDs from UAB

Advisory Committee Chair

Danny R Welch

Advisory Committee Members

Steven L Carroll

Andra A Frost

Clinton J Grubbs

Coral A Lamartiniere

Rosa A Serra

Document Type

Dissertation

Date of Award

2011

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Morbidity and mortality of breast cancer patients are drastically increased when primary tumor cells metastasize to distant organ sites. 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 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. Thus Brms1 transgenic mice (derived on C57BL/6 background) were generated by utilizing MMTV promoter expression (for mammary-selective overexpression) or the beta-actin promoter (for ubiquitous Brms1 overexpression) fused to Brms1 cDNA. The goal of this study was to investigate mechanisms of Brms1- mediated metastasis suppression in transgenic mice that express Brms1 using polyoma middle T (PyMT) oncogene-induced models. Brms1 expression did not significantly alter onset or growth of the primary tumors. When expressed ubiquitously, Brms1 suppressed pulmonary metastasis and promoted apoptosis of tumor cells located in the lungs but not in the mammary glands. Ubiquitous Brms1 overexpression also altered cytokine signaling in primary tumors, a phenomenon that has not been previously reported. Surprisingly, selective expression of Brms1 in the mammary gland using the MMTV promoter did not significantly block metastasis nor did it promote apoptosis in lungs. To determine the impact of host genetic background on Brms1-mediated metastasis suppression, congenic PyMT mice were crossed with Brms1 transgenic mice. Brms1 expression did not significantly alter primary tumor onset or growth. Ubiquitous Brms1 overexpression suppressed metastasis when compared to control littermates, though not significantly. Interestingly, there was no development of metastasis when Brms1 was overexpressed selectively in mammary glands of congenic crossed mice. These results show that tissue- or cell type-specific over-expression of Brms1 is important for Brms1-mediated metastasis suppression. Brms1-mediated apoptosis at secondary tissue sites may be a potential mechanism of metastasis suppression. Additionally, these results suggest that Brms1-mediated metastasis suppression is dependent on host genetic background. Understanding tissue- or cell-specific expression of Brms1 and how host genetics modify Brms1 function will be a major advance to enable correct interpretation of clinical samples.

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