Integrated MicroRNA–mRNA Profiling Identifies Oncostatin M as a Marker of Mesenchymal-Like ER-Negative/HER2-Negative Breast Cancer

Abstract

MicroRNAs (miRNAs) simultaneously modulate different oncogenic networks, establishing a dynamic system of gene expression and pathway regulation. In this study, we analyzed global miRNA and messenger RNA (mRNA) expression profiles of 17 cell lines representing different molecular breast cancer subtypes. Spearman’s rank correlation test was used to evaluate the correlation between miRNA and mRNA expression. Hierarchical clustering and pathway analysis were also performed. Publicly available gene expression profiles (n = 699) and tumor tissues (n = 80) were analyzed to assess the relevance of key miRNA-regulated pathways in human breast cancer. We identified 39 significantly deregulated miRNAs, and the integration between miRNA and mRNA data revealed the importance of immune-related pathways, particularly the Oncostatin M (OSM) signaling, associated with mesenchymal-like breast cancer cells. OSM levels correlated with genes involved in the inflammatory response, epithelial-to-mesenchymal transition (EMT), and epidermal growth factor (EGF) signaling in human estrogen receptor (ER)-negative/human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Our results suggest that the deregulation of specific miRNAs may cooperatively impair immune and EMT pathways. The identification of the OSM inflammatory pathway as an important mediator of EMT in triple-negative breast cancer (TNBC) may provide a novel potential opportunity to improve therapeutic strategies.

Co-Expression of VEGF and IL-6 Family Cytokines is Associated with Decreased Survival in HER2 Negative Breast Cancer Patients: Subtype-Specific IL-6 Family Cytokine-Mediated VEGF Secretion

“…This data demonstrate clear statistical significance for breast cancer patients with HER2-, but not HER2+ status. This was further supported by our in vitro analyses showing that untreated HER2+ BT474 breast cancer cells constitutively express a basal level of VEGF [62] and that OSM had no additional effect on the induction of VEGF secretion in HER2+ cells such as BT474, SK-BR-3, and MDA-MB-453. These findings may suggest redundancy between HER2 and inflammatory cytokine-induced signaling, with most IDC tumors requiring overactivation of only one or the other pathway.…”

MicroRNA-138 is a Prognostic Biomarker for Triple-Negative Breast Cancer and Promotes Tumorigenesis via TUSC2 repression

“…An array of studies has been published on miRNA signatures in TNBC that have elucidated the roles of miRNAs in the progression or suppression of tumors. A number of them are overexpressed, namely miR-221, miR-222, miR-100, miR-146a, miR-125b 11–14 , miR-29a, miR-31, miR-130a, miR-140-3p, miR-455, miR-199a/b-3p 14 , miR-135-5p, miR-18-5p, miR-9-5p, miR-522-3p 15 , while miRNA genes like miR-26a 16 , miR-20a-5p 17 , miR-124 18 , miR-200, miR-182, miR-141, miR-375, miR-203 11–13 , miR-190-5p, miR-449a 15 , 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.…”

miR-3178 inhibits cell proliferation and metastasis by targeting Notch1 in triple-negative breast cancer

“…miRNAs are involved in the tumor initiation, progression, diagnostic, prognostic, and therapeutic potential of TNBC 21 . Moreover, they play important roles in regulating the EMT in breast cancer 22 . The miR-200 family, which inhibits EMT, tumor proliferation, migration, invasion, is downregulated in TNBC 22 , 23 .…”

“…Moreover, they play important roles in regulating the EMT in breast cancer 22 . The miR-200 family, which inhibits EMT, tumor proliferation, migration, invasion, is downregulated in TNBC 22 , 23 . Similarly, miR-205, which is downregulated in TNBC, also can reduce proliferation and inhibit EMT 24 .…”