Abstract B99: Dysregulation of HMGCR and the mevalonate pathway in human cancers

Abstract

Abstract The importance of cancer metabolism has been appreciated for many years, but the intricacies of how metabolic pathways and oncogenic events overlap remains unclear. By understanding how metabolism contributes to tumorigenesis, we will be able to target these fundamental biochemical pathways and impact patient care. The mevalonate (MVA) pathway, paced by its rate-limiting enzyme, hydroxymethylglutaryl coenzyme A reductase (HMGCR), is a metabolic pathway required for the generation of a number of fundamental end-products including cholesterol and isoprenoids. Despite being subject to years of extensive research from the perspective of coronary artery disease, the contribution of the MBA pathway to human cancer remains largely unexplored. Intriguingly, we show that high mRNA levels of 5/6 MVA pathway genes, including HMGCR, correlate with poor prognosis in a meta-analysis of six large expression microarray datasets of primary breast cancer. Indeed, we show that deregulated expression of HMGCR, full-length or splice-variant, increases anchorage-independent growth and tumorigenesis of transformed cells when plated in soft agar or grown as xenografts, respectively. Moreover, we also show that ectopic expression of deregulated HMGCR drives tumorigenesis of non-transformed breast cells a well as normal murine myeloid progenitors. Advancing these studies to an independent tumor-type (multiple-myeloma), shows that loss of the classic feedback response to the blockbuster drugs known as statins, which inhibit HMGCR, further defines dysregulation of the MVA pathway. In addition, we show that this loss of feedback regulation distinguishes the subset of tumor cells that are highly sensitive to statin-induced apoptosis. Taken together, our results suggest that HMGCR is a candidate metabolic oncogene and provides molecular rationale for further exploring HMGCR inhibitors as anticancer agents. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B99.