Proper relocation of a tumor suppressor in Breast Cancer
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: BRCA1 is the first breast cancer susceptibility gene to be identified as a tumor suppressor gene. The BRCA1 gene is either completely absent or mutated in over 80% of families with high rates of early-onset breast and ovarian cancer. While the identification of this gene is a major breakthrough in the study of breast cancer, a role for BRCA1 in sporadic breast tumors, which account for 95% of all breast cancer cases in Europe and North America, has been questionable since these tumors have normal BRCA1 genes. Recently, the BRCA1 protein was found to be completely missing from the nucleus in the majority of breast cancer biopsies examined and in most breast and ovarian cancer cell lines. The nucleus is a compartment of the cell where chromosomes are located and where genes important for cell growth and division are carefully regulated. Although the proper localization of BCRA1 is still under investigation, at least some BCRA1 protein is normally located in the nucleus. This finding, though preliminary, suggests that displacement of BRCA1 from the nucleus results from, or contributes to, the tumorigenic transformation of mammary cells, including sporadic tumors. Its role in this more common form of breast cancer should be reconsidered. Secondly, this observation suggests the possibility that forcing BRCA1 back into the nucleus of breast cancer cells might allow BRCA1 to carry out its normal tumor suppressor function and slow cell growth.
 
 
 
 
 
 
 
 Proteins are guided into the cell nucleus in a multistep process that begins with binding of a nuclear import regulator to small nuclear localization signals within the protein. We have recently identified the genes for the two nuclear import factors known to bind such signals in proteins. Our goal is to use the genes for these import factors as tools to identify and study the nuclear transport pathway that normally guides BRCA1 to the nucleus, to search for a nuclear localization signal in BRCA1 protein, and to study its interaction with the nuclear import pathway in breast cancer cells. Since BRCA1 has only very recently been identified, little is known about the normal structure or function of the protein. Nothing is known about how it is normally transported to the nucleus.
 
 
 
 
 
 
 
 Results from the experiments described here will be important to our understanding of the aberrant localization of BRCA1. It may also provide invaluable insight into the progression of breast cancer, since complete misplacement of BRCA1 is most common in end-stage breast cancer. Finally, our goal is to use the results from these experiments to design a modified BRCA1 protein that can readily move into the nucleus. We may then be able to judge whether forced relocalization of BRCA1 protein to the correct cellular compartment helps to restore normal growth control to these cells - a result that would have direct and important relevance in the search for new strategies to treat breast cancers.