Journal article
Integrative analysis of miRNA and gene expression reveals regulatory networks in tamoxifen-resistant breast cancer
Department of Systems Biology, Technical University of Denmark1
University of Copenhagen2
Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark3
Functional Human Variation, Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark4
Regulatory Genomics, Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark5
Tamoxifen is an effective anti-estrogen treatment for patients with estrogen receptor-positive (ER+) breast cancer, however, tamoxifen resistance is frequently observed. To elucidate the underlying molecular mechanisms of tamoxifen resistance, we performed a systematic analysis of miRNA-mediated gene regulation in three clinically-relevant tamoxifen-resistant breast cancer cell lines (TamRs) compared to their parental tamoxifen-sensitive cell line.
Alterations in the expression of 131 miRNAs in tamoxifen-resistant vs. parental cell lines were identified, 22 of which were common to all TamRs using both sequencing and LNA-based quantitative PCR technologies. Although the target genes affected by the altered miRNA in the three TamRs differed, good agreement in terms of affected molecular pathways was observed.
Moreover, we found evidence of miRNA-mediated regulation of ESR1, PGR1, FOXM1 and 14-3-3 family genes. Integrating the inferred miRNA-target relationships, we investigated the functional importance of 2 central genes, SNAI2 and FYN, which showed increased expression in TamR cells, while their corresponding regulatory miRNA were downregulated.
Using specific chemical inhibitors and siRNAmediated gene knockdown, we showed that both SNAI2 and FYN significantly affect the growth of TamR cell lines. Finally, we show that a combination of 2 miRNAs (miR-190b and miR-516a-5p) exhibiting altered expression in TamR cell lines were predictive of treatment outcome in a cohort of ER+ breast cancer patients receiving adjuvant tamoxifen mono-therapy.
Our results provide new insight into the molecular mechanisms of tamoxifen resistance and may form the basis for future medical intervention for the large number of women with tamoxifen-resistant ER+ breast cancer.
Language: | English |
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Publisher: | Impact Journals LLC |
Year: | 2016 |
Pages: | 57239-57253 |
ISSN: | 19492553 |
Types: | Journal article |
DOI: | 10.18632/oncotarget.11136 |
ORCIDs: | 0000-0001-5647-4828 , Gupta, Ramneek and Workman, Christopher |
Antihormonal therapy Breast cancer Endocrine resistance MiRNA-mediated gene regulation SDG 3 - Good Health and Well-being miRNAs
14-3-3 Proteins Antineoplastic Agents, Hormonal Breast Breast Neoplasms Cell Line, Tumor Cohort Studies Drug Resistance, Neoplasm ESR1 protein, human Estrogen Receptor alpha FOXM1 protein, human Female Forkhead Box Protein M1 Gene Expression Profiling Gene Expression Regulation, Neoplastic Gene Regulatory Networks Humans Intracellular Signaling Peptides and Proteins MCF-7 Cells MRFAP1 protein, human MicroRNAs Nuclear Proteins RNA, Small Interfering SNAI2 protein, human Snail Family Transcription Factors Tamoxifen YWHAG protein, human YWHAZ protein, human antihormonal therapy breast cancer endocrine resistance miRNA-mediated gene regulation