Studies have estimated that five to ten percent of breast cancer cases in the United States are linked to inherited mutations, the most common of which are changes in the BRCA1 or BRCA2 genes. Defects in those genes significantly increase a woman's chance of getting breast cancer. Aiming to help unlock the mysteries of that critical genetic pathway is Bing Xia, PhD, a scientist at The Cancer Institute of New Jersey (CINJ), who was just awarded $1.6 million from the National Cancer Institute (NCI), a division of the National Institutes of Health. CINJ is a Center of Excellence of UMDNJ-Robert Wood Johnson Medical School.

The R01 award will support the work of Dr. Xia, an assistant professor of Radiation Oncology and Pharmacology at UMDNJ-Robert Wood Johnson Medical School, on the functions of PALB2, another gene that has a critical function in the same tumor suppression pathway.

BRCA1 and BRCA2 proteins (which are products of the BRCA1 and BRCA2 genes that carry out their functions) are essential to the maintenance and repair of DNA -- the material that makes up one's genes. These proteins also play important roles in controlling cell growth, particularly after DNA damage. These functions are considered critical to preventing normal cells from becoming cancer cells. Therefore defects in BRCA1 or BRCA2 proteins result in approximately a ten-fold increase of lifetime breast cancer risk. Cancer cells that have non-functional BRCA1 and BRCA2 proteins are unable to repair certain types of DNA damage. Scientists hope to exploit such vulnerability through the use of specifically tailored drugs to kill off such cancer cells.

In recent years, Xia and colleagues have discovered that the novel protein PALB2 serves as a major partner of the BRCA2 protein and that it is required in BRCA2 DNA damage response function. By virtue of this essential role in supporting the function of the BRCA2 "tumor suppressor," PALB2 appears to be a tumor suppressor in its own right, according to Xia. He and others have demonstrated that inherited defects in PALB2 cause heightened risk of breast cancer, just as in the case of BRCA2. Xia's team also recently found that PALB2 also binds the other commonly known breast cancer protein BRCA1, and does so in a way that links the two major breast cancer proteins to form a central breast cancer suppression pathway.

In the current project Xia's team will dig deep into the inner working mechanisms by which PALB2 operates in the cell to support BRCA2 function and connect the two BRCA proteins in DNA repair and cell growth control. They also will generate mouse models of PALB2- and BRCA2-associated breast cancer to study the path of breast cancer development and the characteristics of the tumors.

Xia says he is grateful to the NCI for its support and hopes that the results of the study could have a wide-ranging impact. "This research has the potential to yield critical insights into the origin and development of familial breast cancer, and may also shed light on the development of breast cancer in general," he said. "The results and tools generated from this study may also contribute to the rational design of new breast cancer drugs and treatment strategies."

The five-year award period runs through June 30, 2014.

Source
The Cancer Institute of New Jersey