Abstract
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 siRNA-mediated 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.
Highlights
Tamoxifen is a widely used therapy for estrogen receptor alpha-positive (ER+) breast cancer, and has been shown to be highly effective in the adjuvant setting, with 28% reduction in mortality at 15 years of follow-up [1]
We show that a combination of 2 miRNAs exhibiting altered expression in tamoxifen-resistant breast cancer cell lines (TamRs) cell lines were predictive of treatment outcome in a cohort of ER+ breast cancer patients receiving adjuvant tamoxifen mono-therapy
Comparison of miRNA expression profiles of the 3 TamRs vs. MCF-7/S0.5 obtained by quantitative RT-PCR (qPCR) identified a common tamoxifen resistanceassociated signature consisting of 14 upregulated and 8 downregulated miRNAs (Table 1 and Figure 1A)
Summary
Tamoxifen is a widely used therapy for estrogen receptor alpha-positive (ER+) breast cancer, and has been shown to be highly effective in the adjuvant setting, with 28% reduction in mortality at 15 years of follow-up [1]. The side-effects of anti-estrogenic drugs differ and some patients may not be eligible for a given drug due to co-morbidities [2] It is, rational to maintain tamoxifen as an adjuvant treatment option for postmenopausal ER+ breast cancer patients, AIs have been shown to be superior in this group of patients [2]. More than 60% of protein-coding genes undergo post-transcriptional regulation in the form of degradation or translation inhibition through miRNAs [11, 12] Due to their potential to regulate mRNAs through tumor-suppressing or -inducing capacities, miRNAs have recently been investigated to determine their contributions to cancer development and progression [12, 13]. A majority of previous studies have focused on a limited number of miRNAs and have lacked a system-wide view of miRNA-mediated tamoxifen resistance
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