Loss of Estrogen-Regulated MIR135A1 at 3p21.1 Promotes Tamoxifen Resistance in Breast Cancer

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 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 for its transcriptional activation, whereas tamoxifen treatment inhibited expression of miR-135a in ERα breast cancer cells. miR-135a directly targeted and, 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 locus and decreased miR-135a expression promote ERα breast cancer progression and tamoxifen resistance. Loss of miR-135a in breast cancer disrupts an estrogen receptor-induced negative feedback loop, perpetuating disease progression and resistance to therapy. http://cancerres.aacrjournals.org/content/canres/78/17/4915/F1.large.jpg .

Association of germline variation with the survival of women with BRCA1/2 pathogenic variants and breast cancer

“…The genomic locus of rs57025206, 3p21, is frequently deleted in mammary carcinomas, especially in ER-negative and high-grade tumors [42][43][44] . Subsequent research has not been able to name an unequivocal cancer driver gene, even though several candidates have been suggested, including BAP1 and MIR135A 45,46 , which were detected as eQTL variants in our target gene analysis (Supplementary Data 2). However, the topological data suggested that these eQTLs might represent tissue-specific regulatory associations not present in HMEC, and that if the rs57025206related survival effect is mediated via BAP1 or MIR135A, it probably reflects host-tumor interactions.…”

miRNA Expression Profiles in Luminal A Breast Cancer—Implications in Biology, Prognosis, and Prediction of Response to Hormonal Treatment

“…Also, discrepancies between various studies regarding e.g., the role of specific miRNA evaluated by different authors may be associated with their specific focus, demonstrating that different disease settings and study designs yield different candidates [ 74 ]. Regarding the evaluation of the likelihood of recurrence and resistance to therapeutics such as endocrine resistance [ 83 , 88 , 89 ], the expression of miRNAs should be tested in primary tumor sites, ideally in multicenter studies. Moreover, in vitro evaluation might contribute to the functional characterization of specific miRNAs [ 62 ].…”

“…miRNAs are also very promising novel therapeutic approach to sensitize and suppress the growth of TAM-resistant tumors [ 88 ]. Zhang et aldemonstrated downregulatedexpression of miR-135a in ERα+BC cells with acquired TAM resistance; however, the overexpression of miR-135a partially resensitized cells to TAM therapy through the activation of ERK1/2 and AKT pathways and miR-135a targeted genes ESR1 , ESRRA , and NCOA1 [ 89 ]. The same principle was seen in case of miR-27 that increases the levels of ERα [ 90 ].…”

“…As was mentioned above, the dysregulation of miRNAshas been considered as a critical mediator of cancer development and progression [ 89 ]. Although the anti-cancer drugs are initially effective, the clinical benefits from their use are limited by the development of endocrine resistance.…”

“…Although the anti-cancer drugs are initially effective, the clinical benefits from their use are limited by the development of endocrine resistance. An identification of target genes, protein-protein interactions of deregulated miRNAs and new knowledge about the resistance to anti-cancer drugs can give a base for the development of novel therapeutics targeting specific molecules [ 83 , 88 , 89 ].…”