BACKGROUND Trastuzumab is part of the standard treatment for HER-2 positive breast cancer patients, but not all patients respond to trastuzumab. Altered expression levels for microRNAs in cancer cells have been correlated with prognosis and response to chemotherapy. We hypothesized that altered expression levels for miRNAs in plasma are associated with sensitivity to trastuzumab in patients with HER-2 positive breast cancer. METHODS We performed quantitative RT-PCR in plasma samples including breast cancer patients enrolled in a clinical trial of neoadjuvant trastuzumab-based chemotherapy. We analyzed expression levels for miR-210, -21, -29a, and -126 according to the type of response (pCR (n = 18) vs. residual disease (n = 11)). We also compared expression levels of miRNAs in trastuzumab-sensitive and –resistant breast cancer cells derived from BT474 cells and in an independent set of preoperative (n=39) and postoperative plasma (n=30) from 43 breast cancer patients not given any treatment. RESULTS At baseline before neoadjuvant chemotherapy combined with trastuzumab, circulating miR-210 levels were significantly higher in patients who had residual disease than in those who had pathologic CR (P = 0.0359). Mean expression ratio for miR-210 was significantly higher in trastuzumab-resistant BT474 cells and miR-210 expression was significantly higher before surgery than after surgery (P = 0.0297) and in patients whose cancer metastasized to the lymph nodes (P = 0.0030). CONCLUSIONS Circulating miR-210 levels were associated with trastuzumab sensitivity, tumor presence, and lymph node metastases. This suggests that plasma miR-210 may be used to predict and perhaps monitor response to therapies containing trastuzumab.

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BackgroundNon-coding RNAs have been drawing increasing attention in recent years as functional data suggest that they play important roles in key cellular processes. N-BLR is a primate-specific long non-coding RNA that modulates the epithelial-to-mesenchymal transition, facilitates cell migration, and increases colorectal cancer invasion.ResultsWe performed multivariate analyses of data from two independent cohorts of colorectal cancer patients and show that the abundance of N-BLR is associated with tumor stage, invasion potential, and overall patient survival. Through in vitro and in vivo experiments we found that N-BLR facilitates migration primarily via crosstalk with E-cadherin and ZEB1. We showed that this crosstalk is mediated by a pyknon, a short ~20 nucleotide-long DNA motif contained in the N-BLR transcript and is targeted by members of the miR-200 family. In light of these findings, we used a microarray to investigate the expression patterns of other pyknon-containing genomic loci. We found multiple such loci that are differentially transcribed between healthy and diseased tissues in colorectal cancer and chronic lymphocytic leukemia. Moreover, we identified several new loci whose expression correlates with the colorectal cancer patients’ overall survival.ConclusionsThe primate-specific N-BLR is a novel molecular contributor to the complex mechanisms that underlie metastasis in colorectal cancer and a potential novel biomarker for this disease. The presence of a functional pyknon within N-BLR and the related finding that many more pyknon-containing genomic loci in the human genome exhibit tissue-specific and disease-specific expression suggests the possibility of an alternative class of biomarkers and therapeutic targets that are primate-specific.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-017-1224-0) contains supplementary material, which is available to authorized users.

Development of improved RNA interference based strategies is of utmost clinical importance. While siRNA-mediated silencing of EphA2, an ovarian cancer oncogene, results in reduction of tumor growth, we present evidence that additional inhibition of EphA2 by a microRNA further ‘boosts’ its anti-tumor effects. We identified miR-520d-3p as a tumor suppressor upstream of EphA2, whose expression correlated with favorable outcomes in two independent patient cohorts comprising of 647 patients. Restoration of miR-520d-3p prominently decreased EphA2 protein levels, and suppressed tumor growth and migration/invasion both in vitro and in vivo. Dual inhibition of EphA2 in vivo using DOPC nano-liposomes loaded with miR-520d-3p and EphA2-siRNA showed synergistic anti-tumor efficiency and greater therapeutic efficacy than either monotherapy alone. This synergy is atleast in part due to miR-520d-3p targeting EphB2, another Eph receptor. Our data emphasize the feasibility of combined miRNA-siRNA therapy, and will have broad implications for innovative gene silencing therapies for cancer and other diseases.