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

• Published in: Biomedicine & pharmacotherapy Vol. 77; pp. 37 - 44
• Main Authors: Yu, Xinfeng, Li, Ruilian, Shi, Wenna, Jiang, Tao, Wang, Yufei, Li, Cong, Qu, Xianjun
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01-02-2016
• Subjects: Antineoplastic Agents, Hormonal - pharmacology; Apoptosis; Apoptosis - drug effects; Apoptosis Regulatory Proteins - biosynthesis; Autophagy; Beclin-1; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Cell Line, Tumor; Endocrine resistance; Estradiol - analogs & derivatives; Estradiol - pharmacology; Gene Expression Regulation, Neoplastic; Humans; Internal Medicine; MCF-7 Cells; Medical Education; Membrane Proteins - biosynthesis; MicroRNAs - genetics; MiR-21; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; PI3K-AKT-mTOR; PTEN Phosphohydrolase - biosynthesis; Reverse Transcriptase Polymerase Chain Reaction; Tamoxifen - pharmacology; TOR Serine-Threonine Kinases - antagonists & inhibitors; Transfection; PI3K-AKT-mTOR; Endocrine resistance; MiR-21; Autophagy; Apoptosis
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2015.11.005

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.