Profiles of miRNAs matched to biology in aromatase inhibitor resistant breast cancer
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Reiner Hoppe1,2, Ping Fan3, Florian Büttner1,2,4, Stefan Winter1,2, Amit K. Tyagi3, Heather Cunliffe5, V. Craig Jordan3 and Hiltrud Brauch1,2,4
1 Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany
2 University of Tübingen, Tübingen, Germany
3 Department of Breast Medical Oncology, MD Anderson Cancer Center, University of Texas, Houston, TX, USA
4 German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
5 Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
Hiltrud Brauch, email:
Keywords: breast cancer, AI resistance, microRNA profiling, pathway enrichment, E2-inducible apoptosis
Received: March 23, 2016 Accepted: September 02, 2016 Published: September 17, 2016
Aromatase inhibitor (AI) resistance during breast cancer treatment is mimicked by MCF-7:5C (5C) and MCF-7:2A (2A) cell lines that grow spontaneously. Survival signaling is reconfigured but cells are vulnerable to estradiol (E2)-inducible apoptosis. These model systems have alterations of stress related pathways including the accumulation of endoplasmic reticulum, oxidative, and inflammatory stress that occur prior to E2-induced apoptosis. We investigated miRNA expression profiles of 5C and 2A to characterize their AI resistance phenotypes. Affymetrix GeneChip miRNA2.0 arrays identified 184 miRNAs differentially expressed in 2A and 5C compared to E2-free wild-type MCF-7:WS8. In 5C, 34 miRNAs of the DLK1-DIO3 locus and miR-31 were overexpressed, whereas miR-222 was low. TCGA data revealed poor and favorable overall survival for low miR-31 and miR-222 levels, respectively (HR=3.0, 95% CI:1.9-4.8; HR=0.3, 95% CI:0.1-0.6). Targets of deregulated miRNAs were identified using CLIP-confirmed TargetScan predictions. KEGG enrichment analyses for 5C- and 2A-specific target gene sets revealed pathways associated with cell proliferation including insulin, mTOR, and ErbB signaling as well as immune response and metabolism. Key genes overrepresented in 5C- and 2A-specific pathway interaction networks including EGFR, IGF1R and PIK3R1 had lower protein levels in 5C compared to 2A and were found to be differentially modulated by respective miRNA sets. Distinct up-regulated miRNAs from the DLK1-DIO3 locus may cause these attenuative effects as they are predicted to interact with corresponding 3’ untranslated regions. These new miRNA profiles become an important regulatory database to explore E2-induced apoptotic mechanisms of clinical relevance for the treatment of resistant breast cancer.
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