Integrative analysis of miRNA and gene expression reveals regulatory networks in tamoxifen-resistant breast cancer

Tejal Joshi, Daniel Elias, Jan Stenvang, Carla Maria Lourenco Alves, Fei Teng, Maria Bibi Lyng, Anne Elisabeth Lykkesfeldt, Nils Brünner, Jun Wang, Ramneek Gupta, Christopher Workman, Henrik Ditzel

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Abstrakt

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.
OriginalsprogEngelsk
TidsskriftOncotarget
Vol/bind7
Udgave nummer35
Sider (fra-til)57239-57253
ISSN1949-2553
DOI
StatusUdgivet - 2016

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  • Citationsformater

    Joshi, T., Elias, D., Stenvang, J., Alves, C. M. L., Teng, F., Lyng, M. B., Lykkesfeldt, A. E., Brünner, N., Wang, J., Gupta, R., Workman, C., & Ditzel, H. (2016). Integrative analysis of miRNA and gene expression reveals regulatory networks in tamoxifen-resistant breast cancer. Oncotarget, 7(35), 57239-57253. https://doi.org/10.18632/oncotarget.11136