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Treatment and Prevention of Breast Cancer Using Multifunctional Inhibitors of Cholesterol Biosynthesis

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Annual rept. 1 Jun 2013-31 May 2014

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Most human breast cancers are hormone responsive, depending on estrogens and progestins for tumor cell proliferation. Initially, hormone-responsive tumors respond to endocrine therapy, however, most human breast tumors develop resistance to currently used endocrine therapeutic protocols. It is therefore essential that we identify additional molecular targets in the signaling pathways that lead to tumor growth if we are to effectively treat and prevent cancers of the breast. Our goal was to identify alternative targets in the pathway leading to the production of cholesterol, which might be regulated with less toxic inhibitors to control the progression of breast disease. Inhibitors of oxidosqualene cyclase OSC, an enzyme down-stream of HMG CoA-reductase in the cholesterol biosynthetic pathway, effectively arrested breast cancer cell proliferation. In the 2013 Annual Report we discussed several interesting observations establishing that an OSC inhibitor, RO 48-8071 RO is an effective anti-cancer compound. These results are now published and appended as a research article in Breast Cancer Research and Treatment, a highly reputable journal. During our second year of research we have continued these studies and shown that combination therapy involving RO and an estrogen receptor-beta agonist is an extremely effective means of treating breast cancer. We found that estrogen receptor beta is induced and, importantly, that the pro-proliferative estrogen receptor-alpha is destroyed by RO. These studies show for the first time that inhibition of cholesterol biosynthesis using OSC inhibitors is a novel and potent means by which to destroy human breast cancer cells, and, furthermore, that a combination of RO with agonists of estrogen receptor beta is a viable treatment option that should be considered for patients who exhibit estrogen receptor in their biopsies.

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  • Medicine and Medical Research

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