De novo cholesterol biosynthesis: an additional therapeutic target for the treatment of postmenopausal breast cancer with excessive adipose tissue

Abstract

The onset and development of breast cancer in postmenopausal women are associated with closely related individual-dependent factors, including weight gain and high levels of circulating androgens. Adipose tissue is the most peripheral site of aromatase enzyme synthesis; therefore, the excessive accumulation of visceral fat results in increased androgens aromatization and estradiol production that provides the microenvironment favorable to tumorigenesis in mammary epithelial cells expressing estrogen receptors (ERs). Moreover, to meet the increased requirement of cholesterol for cell membrane assembly and the production of steroid hormones to sustain their proliferation, ER-positive cells activate de novo cholesterol biosynthesis and subsequent steroidogenesis. Several approaches have been followed to neutralize the de novo cholesterol synthesis, including specific enzyme inhibitors, statins, and, more recently, metformin. Cumulating evidence indicated that inhibiting cholesterol biosynthesis by statins and metformin may be a promising therapeutic strategy to block breast cancer progression. Unlike antiestrogens and aromatase inhibitors (AIs) which compete for binding to ER and inhibit androgens aromatization, respectively, statins block the production of mevalonic acid by inhibiting the activity of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, and metformin hampers the activation of the sterol regulatory element-binding protein 2 (SREBP2) transcription factor, thus inhibiting the synthesis of several enzymes involved in cholesterol biosynthesis. Noteworthy, statins and metformin not only improve the prognosis of overweight patients with ER-positive cancer but also improve the prognosis of patients with triple-negative breast cancer, the aggressive tumor subtype that lacks, at present, specific therapy.