Transcriptome-based identification of lovastatin as a breast cancer stem cell-targeting drug


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Marco Velasco-Velazquez1,Luz Vásquez-Bochm1,Mireya Velázquez-Paniagua1,Sandra Castro-Vázquez1,Sandra Guerrero-Rodríguez1,Abimael Mondragon-Peralta1,Mayra Pérez-Tapia2,Aliesha González-Arenas1
1National Autonomous University of Mexico,2National Polytechnic Institute

Abstract

Background

Breast cancer is the neoplastic disease with higher mobility and mortality in women worldwide. The Cancer Stem Cell (CSC) model proposes that a subpopulation at the top of the tumor cell hierarchy drives the initiation, maintenance, and therapy response in breast cancer. Consequently, breast CSCs have been pointed as targets for the development of new therapies.

Method

With the goal of repositioning drugs as breast CSC-targeting agents, we compared a breast CSC consensus signature with the transcriptomic changes induced by 1,300+ bioactive compounds using the Connectivity Map (CMap) platform. In vitro biological screening of the selected drugs consisted in evaluation of SOX2-promoter transactivation, mammosphere formation, and ALDH activity in MDA-MB-231 cells. The effect of the best candidate was validated performing Gene Set Enrichment Analysis (GSEA) on an independent dataset from mammary tumor-bearing mice.

Results

Five drugs (fasudil, pivmecillinam, ursolic acid, 16,16-dimethylprostaglandin E2, and lovastatin) induced gene expression signatures anti-correlated to that of breast CSC. Lovastatin reduced SOX2-promoter transactivation, mammosphere-forming efficiency, and the percentage of ALDH+ breast cancer cells. The addition of mevalonate reverted the effects of lovastatin, demonstrating that CSC-targeting by lovastatin is caused by inhibition of its known target, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR). GSEA analysis showed that lovastatin-treated mice display reduced expression in key genes controlling stemness and invasiveness, corroborating our in vitro findings.

Conclusion

Lovastatin induces transcriptional changes that impair the CSC phenotype. Since the pharmacokinetics and toxicology of lovastatin are known, we propose the repurposing of lovastatin as drug with efficacy against breast CSCs.