Abstract
The dysregulation of miRNAs has been increasingly recognized as a critical mediator of cancer development and progression. Here, we show that frequent deletion of the MIR135A1 locus is associated with poor prognosis in primary breast cancer. Forced expression of miR-135a decreased breast cancer progression, while inhibition of miR-135a with a specific miRNA sponge elicited opposing effects, suggestive of a tumor suppressive role of miR-135a in breast cancer. Estrogen receptor alpha (ERα) bound the promoter of MIR135A1 for its transcriptional activation, whereas tamoxifen treatment inhibited expression of miR-135a in ERα+ breast cancer cells. miR-135a directly targeted ESR1, ESRRA, and NCOA1, forming a negative feedback loop to inhibit ERα signaling. This regulatory feedback between miR-135a and ERα demonstrated that miR-135a regulated the response to tamoxifen. The tamoxifen-mediated decrease in miR-135a expression increased the expression of miR-135a targets to reduce tamoxifen sensitivity. Consistently, miR-135a expression was downregulated in ERα+ breast cancer cells with acquired tamoxifen resistance, while forced expression of miR-135a partially resensitized these cells to tamoxifen. Tamoxifen resistance mediated by the loss of miR-135a was shown to be partially dependent on the activation of the ERK1/2 and AKT pathways by miR-135a-targeted genes. Taken together, these results indicate that deletion of the MIR135A1 locus and decreased miR-135a expression promote ERα+ breast cancer progression and tamoxifen resistance.Significance: Loss of miR-135a in breast cancer disrupts an estrogen receptor-induced negative feedback loop, perpetuating disease progression and resistance to therapy.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/17/4915/F1.large.jpg Cancer Res; 78(17); 4915-28. ©2018 AACR.
Highlights
MiRNAs are endogenous short noncoding RNAs that repress gene expression posttranscriptionally, primarily via binding to 30 untranslated regions (30UTR) of cognate mRNA targets [1]
MiR-135a has been reported to promote breast cancer invasion and migration through mediating the depletion of metastasis suppressor, HOXA10 [33]. miR-135a targets a variety of gene transcripts, including those of oncogenes and tumor suppressors, which may account for the observed incongruity in the effects of miR-135a in different cell lines [2]
Our study has further provided a mechanistic link between miR-135a and the activation of ERK1/2 and AKT1 in tamoxifen resistance
Summary
MiRNAs are endogenous short noncoding RNAs that repress gene expression posttranscriptionally, primarily via binding to 30 untranslated regions (30UTR) of cognate mRNA targets [1]. Deregulated miRNA expression plays fundamental roles in breast cancer progression and therapeutic responses [2]. The human chromosome 3p has been reported to exhibit frequent loss of heterozygosity in cancers including breast cancer [3, 5,6,7,8]. MIR135A1, located at chromosome 3p21.1, has been observed to be frequently lost in breast cancer [3]. Approximately 70% of human primary breast cancers express ERa and derive benefit from antiendocrine therapies, intrinsic and acquired resistance is common [10]. Downregulation of miR-135a has been observed in tamoxifen-resistant breast cancer [11, 12] but its functional involvement remains unexplored
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
