Abstract
IntroductionIncreasing evidence indicates that microRNAs (miRNAs) are important players in oncogenesis. Considering the widespread use of aromatase inhibitors (AIs) in endocrine therapy as a first-line treatment for postmenopausal estrogen receptor α–positive breast cancer patients, identifying deregulated expression levels of miRNAs in association with AI resistance is of utmost importance.MethodsTo gain further insight into the molecular mechanisms underlying the AI resistance, we performed miRNA microarray experiments using a new model of acquired resistance to letrozole (Res-Let cells), obtained by long-term exposure of aromatase-overexpressing MCF-7 cells (MCF-7aro cells) to letrozole, and a model of acquired anastrozole resistance (Res-Ana cells). Three miRNAs (miR-125b, miR-205 and miR-424) similarly deregulated in both AI-resistant cell lines were then investigated in terms of their functional role in AI resistance development and breast cancer cell aggressiveness and their clinical relevance using a cohort of 65 primary breast tumor samples.ResultsWe identified the deregulated expression of 33 miRNAs in Res-Let cells and of 18 miRNAs in Res-Ana cells compared with the sensitive MCF-7aro cell line. The top-ranked Kyoto Encyclopedia of Genes and Genomes pathways delineated by both miRNA signatures converged on the AKT/mTOR pathway, which was found to be constitutively activated in both AI-resistant cell lines. We report for the first time, to our knowledge, that ectopic overexpression of either miR-125b or miR-205, or the silencing of miR-424 expression, in the sensitive MCF-7aro cell line was sufficient to confer resistance to letrozole and anastrozole, to target and activate the AKT/mTOR pathway and to increase the formation capacity of stem-like and tumor-initiating cells possessing self-renewing properties. Increasing miR-125b expression levels was also sufficient to confer estrogen-independent growth properties to the sensitive MCF-7aro cell line. We also found that elevated miR-125b expression levels were a novel marker for poor prognosis in breast cancer and that targeting miR-125b in Res-Let cells overcame letrozole resistance.ConclusionThis study highlights that acquisition of specific deregulated miRNAs is a newly discovered alternative mechanism developed by AI-resistant breast cancer cells to achieve constitutive activation of the AKT/mTOR pathway and to develop AI resistance. It also highlights that miR-125b is a new biomarker of poor prognosis and a candidate therapeutic target in AI-resistant breast cancers.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-015-0515-1) contains supplementary material, which is available to authorized users.
Highlights
Increasing evidence indicates that microRNAs are important players in oncogenesis
Among the molecular mechanisms involved in the acquisition of endocrine resistance, a switch from steroid signaling to growth factor signaling pathways has been the focus of recent studies, which have demonstrated the activation of the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin and/or mitogen-activated protein kinase (MAPK) pathways, both in breast cancer cell lines and in breast tumors [2,3,4,5,6,7,8]
The Res-Let cells displayed complete resistance to letrozole (Figure 1C) and, despite being selected under letrozole exposure only, significantly decreased sensitivity to anastrozole, suggesting, at least in part, common mechanisms of resistance (Figure 1D). As both ER-independent [2,10] and ER-dependent [39,40,41] mechanisms have been described in long-term Aromatase inhibitor (AI) resistance models, we investigated whether the AI resistance acquired by the Res-Let cells was due to any changes in aromatase function, estrogen receptor α (ERα) expression or ERα activity
Summary
Increasing evidence indicates that microRNAs (miRNAs) are important players in oncogenesis. Among the molecular mechanisms involved in the acquisition of endocrine resistance, a switch from steroid signaling to growth factor signaling pathways has been the focus of recent studies, which have demonstrated the activation of the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) and/or mitogen-activated protein kinase (MAPK) pathways, both in breast cancer cell lines and in breast tumors [2,3,4,5,6,7,8] Activation of these survival pathways may contribute to endocrine resistance via the activation of kinases in an ER-dependent [9] as well as ER-independent fashion [2,10]
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