Molecular Analysis of BRCA1 Function

Institution: Salk Institute for Biological Studies
Investigator(s): Mark Chapman, Ph.D. -
Award Cycle: 1997 (Cycle III) Grant #: 3FB-0127 Award: $75,045
Award Type: Postdoctoral Fellowship
Research Priorities
Biology of the Breast Cell>Pathogenesis: understanding the disease

Initial Award Abstract (1997)
A gene called BRCA1 normally acts to prevent breast and ovarian cancer. Individuals with mutations (genetic changes) in this gene have a very high risk of breast cancer, as well as ovarian cancer. The BRCA1 gene was isolated two years ago, which allows for study of the BRCA1 protein that the gene encodes. Currently, it is not known exactly how BRCA1 prevents cancer. It appears to act by controlling cell growth in breast tissue, and in the ovaries, since uncontrolled cell growth results in cancer. I have shown that the BRCA1 protein may be a transcription factor, which is a type of protein that regulates how much of certain other proteins are made. Since BRCA1 is such an important gene in breast cancer, it is important to know how it works. To show that BRCA1 works as a transcription factor, I need to show that this function is important for BRCA1 to control cell growth. I will do this by using cells grown in flasks and making changes to BRCA1 that affect its function as a transcription factor. I will then ask whether these changes also affect how BRCA1 controls cell growth. If BRCA1 is really a transcription factor, then changes that make it a worse transcription factor should also make it worse at controlling cell growth. Similarly, changes that make BRCA1 a better transcription factor should make it better at limiting cell growth. I will also try to identify which proteins might be regulated by BRCA1, since these genes may also be important for preventing breast cancer.

Final Report (1999)
Two genes, BRCA1 and BRCA2, have been identified which normally act to suppress breast and ovarian tumors. Women with mutations in either of these genes have a very high risk of cancer. Both of these genes were molecularly cloned in recent years. This allows for the study of the proteins encoded by BRCA1 and BRCA2. It is not known how these proteins prevent tumors, but we hope that by studying their function at a molecular level, we will gain a better understanding of breast cancer, and ultimately its prevention and treatment.

We have previously shown that BRCA1 may play a role in transcriptional regulation, meaning that it might control the levels of certain other proteins produced within the cell. Other evidence suggests that BRCA1 (and BRCA2) may be involved in preventing uncontrolled cell growth following DNA damage. A potential link between the transcriptional regulatory function of BRCA1 and its role in response to DNA damage was made by other groups which demonstrated that some proteins within the p53 tumor suppression pathway were regulated by BRCA1. However, we have found that both normal and mutant BRCA1 have similar effects on this pathway, indicating that additional pathways are probably involved.

A focus of our recent work has been to identify proteins that physically interact with BRCA1 and BRCA2 within the cell. Identification of such proteins is an important step in understanding BRCA1 and BRCA2 function, in that it provides more experimental tools to test hypotheses. We have identified two new proteins, and our current experiments are aimed at determining the potential role of their interactions with BRCA1 and BRCA2 in tumor suppressing mechanisms. Significant progress is now being made in understanding how both BRCA1 and BRCA2 suppress breast tumors, both in our laboratory and several others. Continued research on these important proteins should help us to understand what can be done to help women who carry mutations in these genes, as well as provide additional information for individuals considering genetic testing. Finally, we hope that such research will lead to a better general understanding of breast tumors as well as other forms of cancer.