Abstract
Breast cancer manifests as a spectrum of subtypes with distinct molecular signatures, and different responses to treatment. Of these subtypes, triple-negative breast cancer (TNBC) has the worst prognoses and limited therapeutic options. Here we report aberrant expression of microRNA-138 (miR-138) in TNBC. Increased miR-138 expression is highly specific to this subtype, correlates with poor prognosis in patients, and is functionally relevant to cancer progression. Our findings establish miR-138 as a specific diagnostic and prognostic biomarker for TNBC. OncomiR-138 is pro-survival; sequence-specific miR-138 inhibition blocks proliferation, promotes apoptosis and inhibits tumour growth in-vivo. miR-138 directly targets a suite of pro-apoptotic and tumour suppressive genes, including tumour suppressor candidate 2 (TUSC2). miR-138 silences TUSC2 by binding to a unique 5′-UTR target-site, which overlaps with the translation start-site of the transcript. Over-expression of TUSC2 mimics the phenotype of miR-138 knockdown and functional rescue experiments confirm that TUSC2 is a direct downstream target of miR-138. Our report of miR-138 as an oncogenic driver in TNBC, positions it as a viable target for oligonucleotide therapeutics and we envision the potential value of using antimiR-138 as an adjuvant therapy to alleviate this therapeutically intractable cancer.
Highlights
Www.nature.com/scientificreports years), progress rapidly, and are more likely to metastasize to the brain and viscera relative to HER2 + cancers[5]
A screen from 544 breast cancer patients in The Cancer Genome Atlas (TCGA) database revealed that triple-negative breast tumours express significantly higher levels of miR-138 than luminal tumours, HER2 + tumours, or healthy breast tissue (TNBC: n = 52, luminal: n = 345, triple-negative breast cancer (TNBC) vs luminal p < 0.0001, Fischer’s exact test; Fig. 1A)
Triple negative breast cancer is considered incurable with limited therapeutic options, highlighting a dire need for therapeutic targets and predictive biomarkers
Summary
Www.nature.com/scientificreports years), progress rapidly, and are more likely to metastasize to the brain and viscera relative to HER2 + cancers[5]. A number of them are overexpressed, namely miR-221, miR-222, miR-100, miR-146a, miR-125b11–14, miR-29a, miR-31, miR-130a, miR-140-3p, miR-455, miR-199a/b-3p14, miR-135-5p, miR-18-5p, miR-9-5p, miR-522-3p15, while miRNA genes like miR-26a16, miR20a-5p17, miR-12418, miR-200, miR-182, miR-141, miR-375, miR-20311–13, miR-190-5p, miR-449a15, have reduced expression in TNBC tumours Among this list of differentially expressed miRNAs, we have previously demonstrated oncogenic potential for miR-138 in recurrent malignant gliomas, and were interested in exploring its roles in the context of breast cancer. We present our finding that miR-138 is a specific molecular signature of triple-negative breast cancers. It is expressed in cells and tissues derived from triple-negative carcinomas and absent in both luminal and HER2 + breast cancers. In vivo tumour formation is inhibited by miR-138 knockdown, suggesting that targeted therapy may unlock new strategies for the management of triple-negative breast cancers with improved patient outcome
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