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

• Published in: Pharmacological reports 2019-06, Vol.71 (3), p.535-544
• Main Authors: Vásquez-Bochm, Luz X., Velázquez-Paniagua, Mireya, Castro-Vázquez, Sandra S., Guerrero-Rodríguez, Sandra L., Mondragon-Peralta, Abimael, De La Fuente-Granada, Marisol, Pérez-Tapia, Sonia M., González-Arenas, Aliesha, Velasco-Velázquez, Marco A.
• Format: Article
• Language: English
• Subjects: Animals; Breast cancer stem cells; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Cell Line, Tumor; Down-Regulation - drug effects; Down-Regulation - genetics; Drug Delivery Systems - methods; Drug repurposing; Drug Safety and Pharmacovigilance; Female; HMGCR inhibitor; Humans; Lovastatin; Lovastatin - pharmacology; Mice; Neoplasm Recurrence, Local - drug therapy; Neoplasm Recurrence, Local - genetics; Neoplastic Stem Cells - drug effects; Original Article; Pharmacotherapy; Pharmacy; Promoter Regions, Genetic - drug effects; Promoter Regions, Genetic - genetics; SOXB1 Transcription Factors - genetics; Transcriptional Activation - drug effects; Transcriptional Activation - genetics; Transcriptome - drug effects; Transcriptome - genetics
• ISSN: 1734-1140; 2299-5684
• DOI: 10.1016/j.pharep.2019.02.011

Breast cancer is a neoplastic disease with high morbidity and mortality in women worldwide. Breast cancer stem cells (CSCs) have a significant function in tumor growth, recurrence, and therapeutic resistance. Thus, CSCs have been pointed as targets of new therapies for breast cancer. Herein, we aimed to repurpose certain drugs as breast CSC-targeting agents. We compared a consensus breast CSC signature with the transcriptomic changes that were induced by over 1300 bioactive compounds using Connectivity Map. The effects of the selected drugs on SOX2 promoter transactivation, SOX2 expression, viability, clonogenicity, and ALDH activity in breast cancer cells were analyzed by luciferase assay, western blot, MTT assay, mammosphere formation assay, and ALDEFLUOR® test, respectively. Gene Set Enrichment Analysis (GSEA) was performed using the gene expression data from mammary tumors of mice that were treated with lovastatin. Five drugs (fasudil, pivmecillinam, ursolic acid, 16,16-dimethylprostaglandin E2, and lovastatin) induced signatures that correlated negatively with the query CSC signature. In vitro, lovastatin inhibited SOX2 promoter transactivation, and reduced the efficiency of mammosphere formation and the percentage of ALDH+ cells. Mevalonate mitigated the effects of lovastatin, suggesting that the targeting of CSCs by lovastatin was mediated by the inhibition of its reported target, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR). By GSEA, lovastatin downregulated genes that are involved in stemness and invasiveness in mammary tumors, corroborating our in vitro findings. Lovastatin is a breast CSC-targeting drug. The inhibition of HMGCR might develop new adjuvant therapeutic strategies for breast tumors.