Comprehensive transcriptomic analysis of heat shock proteins in the molecular subtypes of human breast cancer

Abstract

BackgroundHeat Shock Proteins (HSPs), a family of genes with key roles in proteostasis, have been extensively associated with cancer behaviour. However, the HSP family is quite large and many of its members have not been investigated in breast cancer (BRCA), particularly in relation with the current molecular BRCA classification. In this work, we performed a comprehensive transcriptomic study of the HSP gene family in BRCA patients from both The Cancer Genome Atlas (TCGA) and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohorts discriminating the BRCA intrinsic molecular subtypes.MethodsWe examined gene expression levels of 1097 BRCA tissue samples retrieved from TCGA and 1981 samples of METABRIC, focusing mainly on the HSP family (95 genes). Data were stratified according to the PAM50 gene expression (Luminal A, Luminal B, HER2, Basal, and Normal-like). Transcriptomic analyses include several statistical approaches: differential gene expression, hierarchical clustering and survival analysis.ResultsOf the 20,531 analysed genes we found that in BRCA almost 30% presented deregulated expression (19% upregulated and 10% downregulated), while of the HSP family 25% appeared deregulated (14% upregulated and 11% downregulated) (|fold change| > 2 comparing BRCA with normal breast tissues). The study revealed the existence of shared HSP genes deregulated in all subtypes of BRCA while other HSPs were deregulated in specific subtypes. Many members of the Chaperonin subfamily were found upregulated while three members (BBS10, BBS12 and CCTB6) were found downregulated. HSPC subfamily had moderate increments of transcripts levels. Various genes of the HSP70 subfamily were upregulated; meanwhile, HSPA12A and HSPA12B appeared strongly downregulated. The strongest downregulation was observed in several HSPB members except for HSPB1. DNAJ members showed heterogeneous expression pattern. We found that 23 HSP genes correlated with overall survival and three HSP-based transcriptional profiles with impact on disease outcome were recognized.ConclusionsWe identified shared and specific HSP genes deregulated in BRCA subtypes. This study allowed the recognition of HSP genes not previously associated with BRCA and/or any cancer type, and the identification of three clinically relevant clusters based on HSPs expression patterns with influence on overall survival.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4621-1) contains supplementary material, which is available to authorized users.

HSPA2 Chaperone Contributes to the Maintenance of Epithelial Phenotype of Human Bronchial Epithelial Cells but Has Non-Essential Role in Supporting Malignant Features of Non-Small Cell Lung Carcinoma, MCF7, and HeLa Cancer Cells

“…Accordingly, immunohistochemistry-based studies linked a high level of HSPA2 in tumor with unfavorable clinicopathological characteristics and shorter overall as well as disease-free survival [ 27 , 47 ]. Instead, analysis of the transcriptomic data showed that a high level of HSPA2 mRNA predicts a favorable outcome [ 48 , 49 , 50 ]. Thus, uncertainty as to the value of HSPA2 as a cancer biomarker underlines the necessity to use validated and reliable tools for HSPA2 detection in tumor samples.…”

SPINK7 Expression Changes Accompanied by HER2, P53 and RB1 may be Potential Biomarkers to Predict Oral Squamous Cell Carcinoma at Molecular Level

“…MeanwhileTP53,RB1, NFKB and CYP4B1 were significantly upregulated at OSCC stages compare with dysplasia and control groups.The results obtained by SPINK7 in our study population were compared with a cohort of 541 patients from the TGCA database (47).The comparative analysis showed that SPINK7 was significantly down regulated in patients with OSCC compare to normal tissue and this could be related with the advance grade of the malignant lesion (44). Additionally, we analyzed the mutation profile of genes described in TCGA altered in OSCC included SPINK7, TP53, RB1, NFKB and CYP4B1.…”

HSF1: Primary Factor in Molecular Chaperone Expression and a Major Contributor to Cancer Morbidity

“…Apparent constitutive activation of the HSR pathway in cancer was first indicated by studies in the 1980s that found altered levels of HSPs in transformed cells, as reviewed in [8,9]. The extent to which HSP expression is altered in specific cancer types has since been shown to apply differentially across specific HSP family members and was recently shown at the transcriptomic level in human breast tumors [10]. HSPs play a multitude of roles in tumorigenesis, properties that have underscored the importance of understanding the basis of HSR activation in human cancers, as reviewed in [11,12].…”