MiR-214 increases the sensitivity of breast cancer cells to tamoxifen and fulvestrant through inhibition of autophagy

Abstract

BackgroundTamoxifen (TAM) and fulvestrant (FUL) are the major drugs for patients with estrogen receptor-positive (ER+) breast cancers. However, the development of endocrine resistance is the impediment for successful treatment. We aimed to explore the mechanisms of endocrine resistance and therapeutic strategy for overcoming resistance against TAM and FUL.MethodsExperiments were performed in ER+ and estrogen/TAM-sensitive MCF7 cells and antiestrogen-resistant MCF7/LCC9 cells. The expression of miR-214 and uncoupling protein 2 (UCP2) was determined by RT-qPCR and Western blot in breast cancer cells and human breast cancer tissue specimens. Cell autophagy was examined by fluorescent probe monodansyl cadaverine (MDC) and GFP-LC3-II-positive punctate identified by confocal microscopy. Apoptotic cells were determined by Annexin V-FITC/PI staining. The potential regulatory target of miR-214 was determined by prediction tool, target protein expression and luciferase reporter assay.Results4-OHT/FUL treatment resulted in induction of apoptosis as well as autophagy in breast cancer cells. Autophagy might be the major cause of endocrine resistance to 4-OHT or FUL. MiR-214 increased the sensitivity of breast cancer cells to the 4-OHT/FUL-induced apoptosis through inhibition of autophagy. Importantly, a negative correlation was established between miR-214 and UCP2 in human breast cancer tissue specimens assayed by RT-qPCR. UCP2 was identified to be a direct target of miR-214. Further study in MCF7/LCC9 cells indicated that endocrine resistance might arise from activation of the PI3K-Akt-mTOR pathway, thereby inducing autophagy by overexpression of UCP2.ConclusionMiR-214 increased the sensitivity of breast cancer cells to TAM and FUL through inhibition of autophagy by targeting UCP2. MiR-214 shows potential as a novel therapeutic strategy for overcoming endocrine resistance in ER+ breast cancers.

IL‐1 induces p62/SQSTM1 and autophagy in ERα+/PR+ BCa cell lines concomitant with ERα and PR repression, conferring an ERα−/PR− BCa‐like phenotype

“…We show that IL‐1 signaling mediates HS‐5 BMSC repression of ERα and PR levels concomitant with p62 upregulation and autophagy induction in ERα + /PR + BCa cell lines (Figures ); and we contend that IL‐1‐induced p62 upregulation and autophagy induction also contribute to BCa cell survival, growth, and endocrine resistance when hormone receptors are repressed. In support of this notion, knockout or silencing of p62 or autophagy have been shown to prevent BCa initiation, progression, or metastasis in mouse models and in vitro studies demonstrate that autophagy is cytoprotective against endocrine therapy …”

Clarifying the molecular mechanism associated with carfilzomib resistance in human multiple myeloma using microarray gene expression profile and genetic interaction network

“…According to our bioinformatics analysis, MTOR , EGFR , ERBB2 , PDGFA , PDGFRA and PDGFRB were involved in the subnetwork of miRNAs in cancer pathways. Since mammalian target of rapamycin (mTOR) inhibition can also induce autophagy,24,25 previous results also support the protective role of autophagy during proteasome inhibition, indicating that mTOR inhibition may desensitize carfilzomib both through inhibition of translation and induction of autophagy by regulation by miRNAs 18…”

Network Analysis of MicroRNAs, Transcription Factors, Target Genes and Host Genes in Human Breast Cancer.

“…Research has shown that miRNAs and genes play significant roles in BC's physiological activity. 25,26 Massive research findings associated with miRNAs and genes are not intuitive enough to determine BC's pathogenesis. A systematic and intuitive research method should be proposed to analyse BC's cause.…”