TY - JOUR
T1 - Transcriptome-based identification of lovastatin as a breast cancer stem cell-targeting drug
AU - Vásquez-Bochm, Luz X.
AU - Velázquez-Paniagua, Mireya
AU - Castro-Vázquez, Sandra S.
AU - Guerrero-Rodríguez, Sandra L.
AU - Mondragon-Peralta, Abimael
AU - De La Fuente-Granada, Marisol
AU - Pérez-Tapia, Sonia M.
AU - González-Arenas, Aliesha
AU - Velasco-Velázquez, Marco A.
N1 - Publisher Copyright:
© 2019 Institute of Pharmacology, Polish Academy of Sciences
PY - 2019/6
Y1 - 2019/6
N2 - 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.
AB - 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.
KW - Breast cancer stem cells
KW - Drug repurposing
KW - HMGCR inhibitor
KW - Lovastatin
UR - http://www.scopus.com/inward/record.url?scp=85064538669&partnerID=8YFLogxK
U2 - 10.1016/j.pharep.2019.02.011
DO - 10.1016/j.pharep.2019.02.011
M3 - Artículo
C2 - 31026757
AN - SCOPUS:85064538669
SN - 2299-5684
VL - 71
SP - 535
EP - 544
JO - Pharmacological Reports
JF - Pharmacological Reports
IS - 3
ER -
