Abstract
Simple SummaryIn this study, we investigated the expression pattern and prognostic significance of the heat shock proteins (HSPs) family members in breast cancer (BC) by using several bioinformatics tools and proteomics investigations. Our results demonstrated that, collectively, HSPs were deregulated in BC, acting as both oncogene and onco-suppressor genes. In particular, two different HSP-clusters were significantly associated with a poor or good prognosis. Interestingly, the HSPs deregulation impacted gene expression and miRNAs regulation that, in turn, affected important biological pathways involved in cell cycle, DNA replication, and receptors-mediated signaling. Finally, the proteomic identification of several HSPs members and isoforms revealed much more complexity of HSPs roles in BC and showed that their expression is quite variable among patients. In conclusion, we elaborated two panels of HSPs that could be further explored as potential biomarkers for BC progression and prognosis.Heat shock proteins (HSPs) are a well-characterized molecular chaperones protein family, classified into six major families, according to their molecular size. A wide range of tumors have been shown to express atypical levels of one or more HSPs, suggesting that they could be used as biomarkers. However, the collective role and the possible coordination of HSP members, as well as the prognostic significance and the functional implications of their deregulated expression in breast cancer (BC) are poorly investigated. Here, we used a systematic multi-omics approach to assess the HSPs expression, the prognostic value, and the underlying mechanisms of tumorigenesis in BC. By using data mining, we showed that several HSPs were deregulated in BC and significantly correlated with a poor or good prognosis. Functional network analysis of HSPs co-expressed genes and miRNAs highlighted their regulatory effects on several biological pathways involved in cancer progression. In particular, these pathways concerned cell cycle and DNA replication for the HSPs co-expressed genes, and miRNAs up-regulated in poor prognosis and Epithelial to Mesenchymal Transition (ETM), as well as receptors-mediated signaling for the HSPs co-expressed genes up-regulated in good prognosis. Furthermore, the proteomic expression of HSPs in a large sample-set of breast cancer tissues revealed much more complexity in their roles in BC and showed that their expression is quite variable among patients and confined into different cellular compartments. In conclusion, integrative analysis of multi-omics data revealed the distinct impact of several HSPs members in BC progression and indicate that collectively they could be useful as biomarkers and therapeutic targets for BC management.
Highlights
Breast cancer (BC) represents the most common type and the leading cause of death of cancer among females and accounts for ~16% of all cancers [1]
Heat shock proteins (HSPs) correlated with poor prognosis and negative co-expressed genes for HSPs correlated with good prognosis) and up-regulated in good prognosis
We showed that the mutation rate was higher in HSP members up-regulated in BC, while a lower mutation rate was detected in HSP members down-regulated in BC
Summary
Breast cancer (BC) represents the most common type and the leading cause of death of cancer among females and accounts for ~16% of all cancers [1]. Breast cancer is a heterogeneous disease with several subtypes of different cellular compositions, molecular alterations, as well as clinical behavior [3,4]. Several factors, such as histological grade, type and size of the tumor, lymph node metastasis, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER), are generally considered as prognostic factors, but are insufficient to provide useful information for clinical management [5,6]. Heat shock proteins (HSPs) are one of the largest groups of molecular chaperones that assist the correct folding of partially folded or denatured proteins and prevent the formation of potential aggregates in the cells, promoting their proteasomal degradation [7]. HSPs were first discovered as stress-inducible proteins against physical (temperature elevation) or chemical (increase or decrease in pH, salinity, or oxygen concentration) stressors, performing a wide range of functional activities: Modulation of their synthesis, regulation of kinases activation, participation in signal transduction pathways and rRNA processing [8]
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