Role of HMG-CoA reductase in growth regulation of breast cancer cells.
Published: 2004
Language: eng
Number of pages: 208
Description: The rate of synthesis of mevalonate by 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase may influence the growth of breast cancer cells. The purpose of this study was to investigate the role of mevalonate in the growth of malignant breast cells, and the contribution of mevalonate regulation to mediation of the chemoprotective effects of some dietary compounds. To study the effect of mevalonate on the growth of mammary tumors in vivo, I developed a methodology for delivery of mevalonate to the mammary glands of mice via subcutaneously implanted mini-osmotic pumps. I determined that mevalonate promotes the growth of mammary tumors derived from MDA-MB-435 human breast cancer cells in nude mice. Mevalonate also increased proliferation of the cancer cells in culture, and promoted S phase entry through increased CDK 2 activity. Based on these findings, I investigated the regulation of HMG-CoA reductase in MCF-7 human breast adenocarcinoma cells in vitro  by dietary factors that have been shown to inhibit the proliferation of cancer cells, and to inhibit HMG-CoA reductase activity in normal tissues. Similar to effects observed in cells treated with statins, the plant isoprenoids beta-ionone and geraniol inhibited proliferation of MCF-7 cells through decreased activity of CDK 2. Although geraniol inhibited HMG-CoA reductase activity, exogenous mevalonate did not restore proliferation in geraniol-inhibited cells. beta-Ionone did not significantly inhibit HMG-CoA reductase activity. A mevalonate-independent mechanism, therefore, mediated growth inhibition by these compounds. I next investigated the regulation of HMG-CoA reductase in MCF-7 cells by genistein, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and found that all three down-regulated reductase, primarily through post-transcriptional effects. In mevastatin-treated cells, genistein and DHA, but not EPA, abrogated the induction of reductase caused by this competitive inhibitor. Dietary genistein, DHA, and EPA may, therefore, exert anti-cancer effects through inhibition of mevalonate synthesis in the breast, and may augment the efficacy of statins. In conclusion, I have found that mevalonate promotes the growth of MDA-MB-435 cells when grown in culture or as tumors in vivo. Geraniol, genistein, DHA, and EPA all down-regulate HMG-CoA reductase in MCF-7 cells and, therefore, may mediate cancer preventive effects through this mechanism.
Notes: Adviser:  Michael Archer.

Thesis (Ph.D.)--University of Toronto, 2004.

Electronic version licensed for access by U. of T. users.

Source: Dissertation Abstracts International, Volume: 65-10, Section: B, page: 5080.