Upregulation of BRCA1 as a Cancer Preventive Strategy
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: Mutations in inherited genes associated with the development of breast cancer, such as BRCA1, have been more frequently identified in young women. However, these mutations account for only 5-10% of all breast cancers. In addition, there is controversy as to which mutations are harbingers of future disease. The need to determine how such genes, mutated or not, may affect the risk of this disease in all women is of vital interest. Clearly, identifying mutations, while a vital link to some diseases, is not the only key to dissecting the interrelationships between susceptibility genes and breast cancer in humans. Female hormone status has been definitively linked to breast cancer risk in women. Pregnancy and lactation are protective while early menarche and childlessness increase risk. 
 
 
 
 
 
 
 
 The intent of this proposal is to develop an understanding of how BRCA1 interacts with female hormones in the mammary gland and how these interactions translate into breast cancer risk. The hypothesis driving my research has the goal of focusing attention on how normal BRCA1 helps to prevent cancer and what preventive strategies can be used to increase its tumor suppressor activity during critical periods in a female’s lifetime. This hypothesis is: In individuals whose BRCA1 alleles both encode normal BRCA, 'hormonal' breast cancer risk factors are associated with BRCA1 expression levels. This hypothesis implies that there exists a minimum level of tumor suppressor gene product that the cell must accumulate to be effective against tumorigenesis. If the levels of tumor suppressors could be increased during susceptible periods in life, then it may be possible to protect the females from developing this disease. 
 
 
 
 
 
 
 
 Direct studies to investigate this question in humans are difficult for practical and ethical reasons. One alternative is to utilize animal models to analyze the interaction between BRCA1, hormone status and breast cancer. Past studies in this laboratory indicate that rat strain susceptibility to mammary cancer is proportional to BRCA1 RNA expression within the mammary gland and dependent upon the hormonal status of the animal. We propose to use surgical techniques to alter the hormonal environment of the female rat. We will utilize RNA and protein measuring techniques to assay BRCA1 activity and then determine how sensitive our rats' mammary cells are to becoming cancerous under these various hormonal conditions. 
 
 
 
 
 
 
 
 Finally, we propose to retrospectively analyze human breast tumor tissue, and where available, normal breast tissue, for BRCA1 activity as well as the activity of several other genes associated with breast cancer risk including p53, and RAD51. This specific aim will take advantage of an ongoing USC study of white patients diagnosed with cancer prior to age 50 with a detailed history of menstrual status and oral contraceptive use. The results could lend critical insight into BRCA1-hormone interactions in the mammary gland and associated breast cancer risk.