Interconnection of Estrogen/Testosterone Metabolism and Mevalonate Pathway in Breast and Prostate Cancers

The metabolic steroid hormones, 17β stradiol (E2) and testosterone play key roles in several functions including carbohydrate, lipid and protein metabolism, cellular signaling, cell proliferation, and cancer promotion. Steroid hormones have long been characterized as cell proliferation and differentiation regulators and are closely related to the development of breast and prostate cancers. Moreover, cholesterol metabolism, mainly in adipose tissue, leads to the production of steroids and cytokines, thus increasing the risk of metabolic syndrome, obesity, and ER+ breast cancer in postmenopausal women. Recent studies also shown that testosterone and E2 increase the levels of key enzymes of the mevalonate pathway, leading to post-translational prenylation and farnesylation of numerous proteins in RAS signaling in several cancers, including breast and prostate cancers. There is accumulating evidence both clinically and experimentally suggesting that changes in the metabolism of cholesterol may also have an important role in carcinogenesis. In this regard, the cells treated with mevalonate in culture showed elevated proliferation. Therefore, investigation on cholesterol as a precursor of steroid hormones has confirmed the effects cholesterol metabolite on breast and prostate cancers. Indeed, recent evidence strongly suggests that the MVA pathway and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCOA) have a crucial regulatory role in cellular proliferation and transformation. Therefore, the use of mevalonate inhibitors decreases the production of several biologically active downstream products of the mevalonate pathway, including cholesterol. Although for approximately 20 years statins have been identified as anticancer agents, recent studies have sparked some controversy. Therefore, further investigation to evaluate mevalonate- dependent therapeutic agents per se and in combination with other agents is merited. The current review is an attempt to elucidate the role of cholesterol and E2/testosterone, as well as the mevalonate pathway and its inhibitors in breast and prostate tissues in normal and pathological states.