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.
Highlights
Breast cancer is a major cause of cancer death in women worldwide
By selecting only miRNAs expressed in at least nine cell lines, we identified 39 miRNAs significantly deregulated between triple-negative/mesenchymal-like and non-mesenchymal-like cells (Benjamini-Hochberg-adjusted p ≤ 0.05)
Hierarchical clustering analysis revealed that the 17 breast cancer cell lines were separated into two main branches based on differences in the expression of the 39 miRNAs (Figure 1)
Summary
Breast cancer is a major cause of cancer death in women worldwide. Recent advancements in the understanding of cancer biology and oncogenic mechanisms have led to the refinement of breast cancer classification, highlighting the molecular and clinical heterogeneity of this disease. Distinct signaling pathways, genetic and epigenetic aberrations, and gene expression profiles have been associated with different breast cancer subtypes [1,2,3,4,5,6,7]. Cancer-related inflammation is recognized as a hallmark of cancer, and anti-tumor immune responses are emerging as important predictors of outcome and response to therapies in TNBC [10,11]. Several molecular messengers, such as chemokines and cytokines, are able to modulate the reciprocal interaction between breast cancer cells and the immune microenvironment, supporting tumor development and progression [10]. Considering the complexity and heterogeneity of breast cancer, the identification of reliable subtype-specific molecules, which function to simultaneously modulate different oncogenic networks, may provide novel insights into the dynamic architecture of cancer-related pathways and an opportunity to optimize therapeutic strategies
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