Cholesterol de novo biosynthesis: a promising target to overcome the resistance to aromatase inhibitors in postmenopausal patients with estrogen receptor-positive breast cancer

Abstract

Aim: Cholesterol is an essential component of cell membranes and serves as a precursor for several bioactive molecules, including steroid hormones and isoprenoids. Generally supplied by the bloodstream, the de novo cholesterol biosynthesis is activated in response to an increased cell requirement due to normal tissue remodeling or tumor proliferation. In estrogen receptor (ER)-positive breast cancers, cholesterol biosynthesis may promote and sustain tumor growth and concur with the failure of the treatment with aromatase inhibitors. Methods: In this study, the comparison of gene compared the expression involved in cholesterol biosynthesis was conducted in ER-positive tumors that were responsive and nonresponsive to letrozole; besides, an exploration of their association with genes implicated in estrogen production, the Hippo pathway, and cell cycle control was performed. Results: In responsive tumors, letrozole significantly decreased the expression of five genes [acetyl-coenzyme A (CoA) acetyltransferase 2 (ACAT2), 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1), 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), farnesyl diphosphate synthase (FDPS), and squalene epoxidase (SQLE)] crucial for the biosynthetic process. Conversely, in nonresponsive tumors, these genes were unaffected by letrozole but associated with several genes involved in estrogens production [cytochrome P450 family 19 subfamily A member 1 (CYP19A1), hydroxysteroid 17-beta dehydrogenase 2 (HSD17B2), and sulfotransferase family 1A member 1 (SULT1A1)], cell cycle [control cyclin dependent kinase 4 (CDK4) and CDK6], and Hippo pathway [Yes1 associated transcriptional regulator (YAP1) and baculoviral inhibitor of apoptosis (IAP) repeat containing 5 (BIRC5)]. Conclusions: The findings corroborated the notion that the dysregulation of the mevalonate pathway may contribute to the resistance to letrozole and supported the use of statins to contrast this metabolic dysfunction.

Keywords

• breast cancer
• aromatase inhibitors
• cholesterol biosynthesis
• hippo signaling pathway