All ETDs from UAB

Advisory Committee Chair

Danny R Welch

Advisory Committee Members

Douglas R Hurst

Joanne Murphy-Ullrich

Selvarangan Ponnazhagan

Ralph D Sanderson

Document Type

Dissertation

Date of Award

2010

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

The majority of cancer related mortality is attributed to complications associated with metastatic disease. Breast cancer metastasis suppressor 1 (BRMS1) suppresses metastasis of multiple cancer types in vivo and loss of nuclear BRMS1 is associated with ER-negative cancers and a high rate of proliferation. Many groups have shown BRMS1 to regulate the expression of multiple metastatic genes, yet until now no one has been able to account for how these many changes in gene expression occur. In this work, we report that BRMS1 regulates a select set of genes called microRNA (miRNA), and these miRNA themselves can regulate metastasis. Using multiple human metastatic breast cancer cell lines, we compared BRMS1 and vector treated cell lines for miRNA populations using miRNA arrays. Remarkably, BRMS1 changed a rather small subset of miRNA and these miRNA have been implicated by our group and others to regulate metastasis. BRMS1 decreased the prometastatic miRNA 10b, 373, and 520c, while increasing the metastasis suppressing miRNA 146a, 146b, and 335. To determine if these changes in miRNA actually contribute toward BRMS1 metastasis suppression, we restored miR-10b expression in cells expressing BRMS1 and observed increased cellular migration and invasion. Furthermore, ectopic expression of miR-146 in metastatic breast carcinoma cells suppressed migration, invasion, and metastasis. In addition to BRMS1 regulating individual miRNA, we observe changes in polycistronic miRNA. The polycistronic miRNA cluster miR-183, -96, -182 increases in cells expressing BRMS1. Thus far, groups have reported both metastasis suppressing and metastasis promoting phenotypes for members of this cluster. We have found that knockdown of this cluster in BRMS1 expressing cells results in increased invasion and migration in metastatic breast cancer cells while over expression inhibits. Taken together, these findings provide further mechanistic insight for how BRMS1 suppresses metastasis, and we provide new possible therapeutic targets for late stage metastatic disease

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