Abstract 871: Synthetic inhibitors of the cholesterol biosynthetic enzyme oxidosqualene cyclase block proliferation and survival of breast cancer cells.

Abstract

Abstract 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. It is well-established that breast cancer cells have the capacity to synthesize endogenous cholesterol, the precursor for steroid hormones. Cholesterol biosynthesis by tumor cells therefore potentially contributes towards anti-hormone resistance. Most commonly used cholesterol lowering drugs inhibit HMG CoA-reductase, a key rate-limiting enzyme in the cholesterol biosynthetic pathway; these inhibitors are however associated with certain undesirable side effects that limit their use for cancer therapy. 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, effectively arrested breast cancer cell proliferation. RO0488071 [4’-[6-(Allylmethylamino)hexyloxy]-4-bromo-2’-fluorobenzophenone fumarate]) (RO), and an analogue RO0613479, were particularly effective in this regard. Administration of both of these OSC inhibitors to ER positive human breast cancer cells (e.g. BT-474, T47-D, MCF-7) at a pharmacological dose or at a dose close to the IC50 value for OSC (nM range) reduced tumor cell viability in vitro. Administration of RO to animals with human breast cancer cell-derived xenografts prevented further in vivo progression of the disease, with no apparent toxicity. Since BT-474 cells are also tamoxifen resistant and rich in Her2/neu, RO appears to be effective in vivo against even the most aggressive anti-hormone resistant tumors. Importantly, RO had no effect on the viability of normal human mammary cells. Our study shows 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, though further studies are necessary to determine the mechanism of RO mediated loss of breast cancer cell viability. Supported by a Dept of Defense Breast Cancer Pgm grant W81XWH-12-1-0191, NIH grant R21 GM088517, and by a COR grant from the University of Missouri, Columbia. Citation Format: Yayun Liang, Xiaoqin Zou, Cynthia Besch-Williford, Aebi Johannes, Salman M. Hyder. Synthetic inhibitors of the cholesterol biosynthetic enzyme oxidosqualene cyclase block proliferation and survival of breast cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 871. doi:10.1158/1538-7445.AM2013-871