The Novel Role of BRIP1 in Breast Tumor Development and Progression

Abstract

Breast cancer (BC) is the most common malignancy and the leading cause of death in women worldwide. Only 5-10% of mutations in the BRCA genes are attributed to familial breast tumors in Eastern countries, suggesting the contribution of other genes to be identified. Pursuant to this goal, our literature search led to the following observations: 1) in a recent study of my supervisor’s team using microarray gene expression profiling of BC in Omani population identified BRIP1 (5 fold upregulation) as a potential gene associated with BC progression; 2) BRIP1 is a tumor suppressor that inhibits cell growth and controls DNA repair mechanisms. Despite its role as a tumor suppressor, the precise role of BRIP1 in breast tumor cell progression has not been explored yet; this prompted us to hypothesize that BRIP1 is upregulated during breast tumorigenesis to promote breast tumor cell proliferation and invasion. Using a combination of cellular and molecular approaches, our results of structural validation experiments showed differential over-expression of BRIP1 in different BC cell lines. Functional assays confirmed the novel role of BRIP1 in malignant phenotype. siRNA Down-regulation of BRIP1 attenuated cell proliferation significantly and induced cell cycle arrest in G1/S phase. Furthermore, siRNA-mediated BRIP1 knockdown significantly reduced both cell migration and invasion by targeting a number of potential cell motility-associated genes. Altogether, our investigation is the first to validate the novel function of BRIP1 in promoting breast tumor cell invasion, and identifying a unique set of pro-invasive genes to predict the mechanisms that underpin BRIP1-promoting BC progression. Ongoing/future experiments combining bioinformatics analysis and functional cell approaches aim to validate the relevance of these genes in BC progression. This is in order to better understand the exact molecular mechanisms that underpin BRIP1-promoting cell invasion, and validate the genes mediating BRIP1 function in cell proliferation and invasion as biomarkers and/or targets to guide the design of appropriate BC targeted therapies.