Abstract
IntroductionAlthough human epidermal growth factor receptor 2 (HER2) positive or estrogen receptor (ER) positive breast cancers are treated with clinically validated anti-HER2 or anti-estrogen therapies, intrinsic and acquired resistance to these therapies appears in a substantial proportion of breast cancer patients and new therapies are needed. Identification of additional molecular factors, especially those characterized by aggressive behavior and poor prognosis, could prioritize interventional opportunities to improve the diagnosis and treatment of breast cancer.MethodsWe compiled a collection of 4,010 breast tumor gene expression data derived from 23 datasets that have been posted on the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database. We performed a genome-scale survival analysis using Cox-regression survival analyses, and validated using Kaplan-Meier Estimates survival and Cox Proportional-Hazards Regression survival analyses. We conducted a genome-scale analysis of chromosome alteration using 481 breast cancer samples obtained from The Cancer Genome Atlas (TCGA), from which combined expression and copy number data were available. We assessed the correlation between somatic copy number alterations and gene expression using analysis of variance (ANOVA).ResultsIncreased expression of each of the heat shock protein (HSP) 90 isoforms, as well as HSP transcriptional factor 1 (HSF1), was correlated with poor prognosis in different subtypes of breast cancer. High-level expression of HSP90AA1 and HSP90AB1, two cytoplasmic HSP90 isoforms, was driven by chromosome coding region amplifications and were independent factors that led to death from breast cancer among patients with triple-negative (TNBC) and HER2-/ER+ subtypes, respectively. Furthermore, amplification of HSF1 was correlated with higher HSP90AA1 and HSP90AB1 mRNA expression among the breast cancer cells without amplifications of these two genes. A collection of HSP90AA1, HSP90AB1 and HSF1 amplifications defined a subpopulation of breast cancer with up-regulated HSP90 gene expression, and up-regulated HSP90 expression independently elevated the risk of recurrence of TNBC and poor prognosis of HER2-/ER+ breast cancer.ConclusionsUp-regulated HSP90 mRNA expression represents a confluence of genomic vulnerability that renders HER2 negative breast cancers more aggressive, resulting in poor prognosis. Targeting breast cancer with up-regulated HSP90 may potentially improve the effectiveness of clinical intervention in this disease.
Highlights
Human epidermal growth factor receptor 2 (HER2) positive or estrogen receptor (ER) positive breast cancers are treated with clinically validated anti-human epidermal growth factor receptor 2 (HER2) or anti-estrogen therapies, intrinsic and acquired resistance to these therapies appears in a substantial proportion of breast cancer patients and new therapies are needed
Analysis of 4,010 breast cancer samples To conduct a genome wide survey for poor prognosisassociated genes in breast cancer, we compiled a collection of breast tumor gene expression data (n = 4,010) derived from 23 datasets that were posted on the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO, Table 1) and normalized by Bayesian Factor Regression Modeling (BFRM) to remove technical variation (Figure 1A; Additional file 2) [26]
We found significant correlations between mRNA expression level and reported HER2, ER or progesterone receptor (PR) status measured by IHC (P < 1 × 10-8, Mann-Whitney U test, Additional file 3), which was consistent with previous reports that ER, HER2 and PR biochemical status was concordant with Affymetrix microarray data [29,30]
Summary
Human epidermal growth factor receptor 2 (HER2) positive or estrogen receptor (ER) positive breast cancers are treated with clinically validated anti-HER2 or anti-estrogen therapies, intrinsic and acquired resistance to these therapies appears in a substantial proportion of breast cancer patients and new therapies are needed. Identification of additional molecular factors, especially those characterized by aggressive behavior and poor prognosis, could prioritize interventional opportunities to improve the diagnosis and treatment of breast cancer. Substantial progress in treatment requires identification of a specific set of actionable genomic abnormalities that drive or facilitate tumorigenesis, resistance to a given treatment and recurrence. Analyses of chromosomal copy number aberrations (CNAs) have been proposed as a critical indicator of the possible location of aggressive cancer phenotype related genes [4,5]. We undertook an integrative analysis of copy number and gene expression in a large population study to identify molecular factors abundant in breast cancer cells, especially in those characterized by aggressive behavior and poor prognosis, by which to prioritize interventional opportunities to transform breast cancer diagnosis, characterization, treatment and prevention
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