Regulation of the Mevalonate Pathway for the Prevention of Breast Cancer
Annual rept. 1 Jul 1999-1 Jul 2000
TORONTO UNIV (ONTARIO)
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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 1, we have shown that the decrease in mammary gland HMG-CoA reductase seen in LDL-R -- mice compared to 1 mice fed a 7 n-6 PUFA diet persists when animals are fed a 20 n-6 PUFA diet. Based on these observations, a long-term experiment is underway to determine whether the lower reductase activity in LDL-R -I- compared to 1 mice will lead to a lower incidence of mammary tumors. In Task 2, we have prepared reagents to create transgenic mice that over-express the LDL-R in the mammary gland. We are also testing the feasibility of using mini-osmotic pumps to deliver mevalonate to the rat mammary gland. Preliminary experiments for Task 3 have shown the feasibility of using normal and neoplastic human breast epithelial cells to investigate the mechanism of growth inhibition by n-3 PUFAs. 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 this disease.
- Medicine and Medical Research