Title:Interconnection of Estrogen/Testosterone Metabolism and Mevalonate Pathway in Breast and Prostate Cancers
Volume: 10
Author(s): Pooneh Mokarram, Javad Alizadeh, Vahid Razban, Mahdi Barazeh, Claudia Solomon and Soudabeh Kavousipour
Affiliation:
Keywords:
Breast tissue, cancer risk, mevalonate pathway, prostate tissue, statins.
Abstract: 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.
