Role of hydroxymethylglutharyl-coenzyme A reductase in the induction of stem-like states in breast cancer

Abstract

Purpose: De novo synthesis of cholesterol and its rate-limiting enzyme, hydroxymethylglutharyl-coenzyme A reductase (HMGCR), is deregulated in tumors and critical for tumor cell survival and proliferation. However, the role of HMGCR in the induction and maintenance of stem-like states in tumors remains unclear. Methods: A compiled public database from breast cancer (BC) patients was analyzed with the web application SurvExpress. The web application Cell Miner was used for the analysis of HMGCR expression and statin sensitivity of the NCI-60 cell lines panel. A CRISPR-on system was used to induce HMGCR overexpression in the luminal BC cell line MCF-7 and a lentiviral pLM-OSKM system for the reprogramming of MCF-7 cells. Comparisons were performed by two-tailed unpaired t-test for two groups and one- or two-way ANOVA. Results: Data from BC patients showed that high expression of several members of the mevalonate pathway were associated with lower recurrence-free survival, particularly in hormone-receptor-positive BC. Cell Miner showed that HMGCR is expressed in several BC cancer cell lines, data validated by qRT-PCR in a BC cell lines panel. BC cells showed a subtype-dependent response to statins in silico and in vitro, partially determined by HMGCR. A stem-like phenotype was demonstrated upon HMGCR expression in MCF-7 cells, characterized by expression of the pluripotency markers NANOG, SOX2, increased CD44+/CD24low/-, CD133+ populations and increased mammosphere formation. Pluripotent and cancer stem cell lines showed high expression of HMGCR whereas cell reprogramming of MCF-7 cells did not increase HMGCR expression. Conclusion: HMCGR is associated with lower recurrence-free survival in BC and with stablished stem states.