Regulation of the Mevalonate Pathway for the Prevention of Breast Cancer
Abstract
The central hypothesis we are addressing is that inhibition of mammary carcinogenesis by n-3 polyunsaturated fatty acids (PUFAs) can be accounted for by their inhibitory effect on the cholesterol biosynthesis (mevalonate) pathway. In Task 3, we have shown that the n-3 PUFA docosahexaenoic acid (DHA) inhibits MCF-7 cell proliferation in part though inhibition of mevalonate synthesis. Mechanisms other than inhibition of mevalonate synthesis, however, appear to be responsible for the inhibitory effects of eicosapentaenoic acid (EPA) on growth of MCF-7 cells. In Task 4 (new), we determined that mevalonate promotes the growth of mammary tumors in nude mice, and of human breast cancer cells in culture. This effect is associated with alterations in Gl regulatory proteins that support initiation of DNA synthesis. This finding has major significance for both prevention and treatment of mammary cancer, since mammary mevalonate synthesis may be increased by common treatments that lower serum cholesterol levels (e.g. use of bile acid sequesterants and statins). Our work will provide a basis for understanding the protective effects of n-3 PUFAS and perhaps other dietary factors on breast cancer development and may lead to mechanism-based strategies for the prevention of breast cancer.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2002
- Accession Number
- ADA407549
Entities
People
- Michael C. Archer
Organizations
- University of Toronto