SAT-300 - Inhibiting cholesterol biosynthesis pathway in TNBC cells suppresses lung metastasis and is associated with reduction of methionine aminopeptidase 2 expression

Triple-negative breast cancer (TNBC) patients have limited treatment options and poor prognosis. TNBC lack ER, PR and Her2neu, proteins that are commonly targeted in breast cancer therapies. As an alternative, those with TNBC are usually administered toxic, non-specific chemotherapeutic agents; however, drug-resistance occurs in about 50% of TNBC sufferers. New non-toxic therapeutic strategies to control TNBC are urgently needed since drug-resistant cells metastasize to other organs. Cholesterol is an essential structural and functional component of cell membranes that is necessary for growth of both primary tumors and metastatic colonies that reside in distant organs. Previously we showed that inhibiting oxidosqualene cyclase (OSC), an enzyme that occurs downstream of HMGCoA-reductase in the cholesterol biosynthetic pathway in TNBC cells, is an attractive therapeutic strategy through which to disrupt tumor growth and metastasis. We used a potent small molecule inhibitor of OSC, RO 48-8071 (4'-[6-(allylmethylamino)hexyloxy]-4-bromo-2'-fluorobenzophenone fumarate) (RO), that has emerged as a useful chemotherapeutic agent for treating several forms of primary tumors, including TNBC (Liang, Y. et al.; J. Cancer Science and Clinical Therapeutics. 8: 119-125. 2024). Recently, we developed a mouse model for studying the effect of RO on lung metastasis using an MDA-MB-231 variant (LM2) TNBC cell line obtained from Dr. Massagu? (Memorial Sloan-Kettering Cancer Center). These are aggressive cells, and injection of only 2 X 105 cells produces lung metastatic colonies in approximately 4-6 weeks. Five days after tumor cell inoculation animals received 20 mg/kg (n=6), 40 mg/kg (n=7) RO (ip) or vehicle alone (n=7) every other day for two weeks. Animals were then sacrificed, and both lungs harvested and immediately fixed in Bouin's fixative. We found that RO significantly reduced lung metastasis without affecting animal weight. Our study is the first to demonstrate that disruption of cholesterol biosynthesis in a model of human TNBC leads to reduced metastasis in lungs. To establish a mechanism for RO mediated inhibition of lung metastasis, we treated MDA-MB-231 and its LM2 variant with RO in vitro and used a metastasis microarray to determine the proteins affected by RO. We found that the pro-angiogenic protein methionine aminopeptidase 2 (MetAp2), which promotes protein synthesis, tumor growth and metastasis, was significantly reduced at both RNA (RT-PCR) and protein levels (Western blot analysis) in RO treated cells. We have thus identified RO as a novel modulator of MetAp2 that should be evaluated in clinical trials as a non-toxic, anti-metastatic drug for suppressing lung metastasis of TNBC.

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