KU Cancer Center Path to NCI Comprehensive Designation

My research has been with the breast cancer susceptibility gene 1 (BRCA1) and breast cancer for more than 20 years. I was part of the team to provide the first evidence that BRCA1 was a tumor suppressor. Currently, our lab has several projects aimed at understanding BRCA1 regulation and how we might enhance the ability of BRCA1 to act as a tumor suppressor.

BRCA1 has been intensely investigated and mutations in the BRCA1 gene have been found to account for half of the hereditary breast cancer cases and almost all hereditary breast and ovarian cancer cases. Although the role of BRCA1 in sporadic breast and ovarian cancer is still uncertain, decreased BRCA1 expression often accompanies sporadic breast cancer progression. However, data published from my lab demonstrates that the overexpression of BRCA1 in the murine mammary gland provides protection against mutagen-induced mammary neoplasia. This work supports the hypothesis that an increase in BRCA1 can provide protection against tumors. Therefore, one project in the laboratory developed a stable human breast cancer cell line containing integrated copies of a BRCA1 promoter-driven luciferase reporter plasmid and screened over 100,000 compounds for their ability to increase BRCA1 expression. The overall objective of this project is to identify a drug that will increase BRCA1 and restore its tumor suppressor activity. This project shows promise for the discovery of a new agent to prevent or treat breast cancer.

Another project in the lab aims to identify cellular components as regulators of BRCA1 expression and function. DNA damage repair is a critical BRCA1 function that has been extensively investigated and is the focus of our cell-based functional assay developed to identify potential regulatory kinases of BRCA1 expression and function. DNA damage leads to the localization of several proteins involved in the repair of DNA, including BRCA1 and these repair sites are visualized as nuclear foci using fluorescence-based microscopy. Additionally, kinases modulate a variety of cell-specific responses, including signal transduction and DNA damage repair. These kinases can be selectively targeted for knockdown using siRNA to investigate the effect of a kinase on BRCA1 foci formation. Changes in either BRCA1 expression or activity will be reflected in observable alterations in BRCA1 foci formation. We have established the experimental parameters of the functional assay and are currently screening an siRNA kinase library for regulators of BRCA1 expression.

Additionally, BRCA1 has been shown to have a role in stem cell regulation. We are furthering those studies to understand the mechanisms behind breast cancer stem cells and expression of BRCA1. 

My lab research aims at understanding BRCA1 regulation, expression and function. We hope our contributions to the BRCA1 and breast cancer fields will ultimately result in new preventative or therapeutic treatment options for breast cancer patients.