title: Silencing of MicroRNA-21 confers the sensitivity to tamoxifen and fulvestrant by enhancing autophagic cell death through inhibition of the PI3K-AKT-mTOR pathway in breast cancer cells.
abstract: Tamoxifen (TAM) and fulvestrant (FUL) represent the major adjuvant therapy to estrogen receptor-alpha positive (ER(+)) breast cancer patients. However, endocrine resistance to TAM and FUL is a great impediment for successful treatment. We hypothesized that miR-21 might alter the sensitivity of breast cancer cells to TAM or FUL by regulating cell autophagy. Using the ER(+) breast cancer cells, we knockdown miR-21.by transfection with miR-21 inhibitor, then the cells were exposed to TAM or FUL and the percentages of apoptosis and autophagy were determined. Knockdown of miR-21 significantly increased the TAM or FUL-induced apoptosis in ER(+) breast cancer cells. Further, silencing of miR-21 in MCF-7 cells enhanced cell autophagy at both basal and TAM or FUL-induced level. The increase of autophagy in miR-21-knockdown MCF-7 cells was also indicated by increase of beclin-1, LC3-II and increased GFP-LC3 dots. Importantly, knockdown of miR-21 contributed to autophagic cell death, which is responsible for part of TAM induced cell death in miR-21 inhibitor-transfected cells. Further analysis suggested that miR-21 inhibitor enhance autophagic cell death through inhibition of PI3K-AKT-mTOR pathway. MiR-21 coordinated the function of autophagy and apoptosis by targeting Phosphatase and tensin homolog (PTEN) through inhibition of PI3K-AKT-mTOR pathway. In conclusion, silencing of miR-21 increased the sensitivity of ER(+) breast cancer cells to TAM or FUL by increasing autophagic cell death. Targeting autophagy-related miRNAs is a potential strategy for overcoming endocrine resistance to TAM and FUL.
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
authors.forename: Xinfeng
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
authors.forename: Ruilian
authors.initials: R
authors.lastname: Li
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, China; Pharmaceutical Department, Tumor Hospital of Shandong Province, Jinan, China.
authors.forename: Wenna
authors.initials: W
authors.lastname: Shi
authors.affiliation: Department of Anesthesiology, Tumor Hospital of Shandong Province, Jinan, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Jiang
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
authors.forename: Yufei
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
authors.forename: Cong
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, China. Electronic address: quxj@ccmu.edu.cn.
authors.forename: Xianjun
authors.initials: X
authors.lastname: Qu
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis; D001343:Autophagy; D000071186:Beclin-1; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077267:Fulvestrant; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D008565:Membrane Proteins / Q000096:biosynthesis; D035683:MicroRNAs / Q000235:genetics*; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D013629:Tamoxifen / Q000494:pharmacology*; D014162:Transfection
chemical_list: D018931:Antineoplastic Agents, Hormonal; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; C524940:MIRN21 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013629:Tamoxifen; D000077267:Fulvestrant; D004958:Estradiol; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: Apoptosis; Autophagy; Endocrine resistance; MiR-21; PI3K-AKT-mTOR