RESUMEN
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: Lovastatin is a breast CSC-targeting drug. The inhibition of HMGCR might develop new adjuvant therapeutic strategies for breast tumors.
Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Lovastatina/farmacología , Células Madre Neoplásicas/efectos de los fármacos , Transcriptoma/efectos de los fármacos , Animales , Línea Celular Tumoral , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/genética , Sistemas de Liberación de Medicamentos/métodos , Femenino , Humanos , Ratones , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Regiones Promotoras Genéticas/efectos de los fármacos , Regiones Promotoras Genéticas/genética , Factores de Transcripción SOXB1/genética , Activación Transcripcional/efectos de los fármacos , Activación Transcripcional/genética , Transcriptoma/genéticaRESUMEN
Cancer Stem Cells (CSCs) constitute a subpopulation at the top of the tumor cell hierarchy that contributes to tumor heterogeneity and is uniquely capable of seeding new tumors. Because of their biological properties, CSCs have been pointed out as therapeutic targets for the development of new therapies against breast cancer. The identification of drugs that selectively target breast CSCs requires a clear understanding of their biological functions and the experimental methods to evaluate such hallmarks. Herein, we review the methods to study breast CSCs properties and discuss their value in the preclinical evaluation of CSC-targeting drugs.