1. SERPINA1 is a direct estrogen receptor target gene and a predictor of survival in breast cancer patients.
- Author
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Chan HJ, Li H, Liu Z, Yuan YC, Mortimer J, and Chen S
- Subjects
- Antineoplastic Agents, Hormonal pharmacology, Binding Sites, Biomarkers, Tumor genetics, Breast Neoplasms genetics, Breast Neoplasms mortality, Breast Neoplasms pathology, Breast Neoplasms therapy, Chromatin Immunoprecipitation, Computational Biology, Databases, Genetic, Enzyme Induction, Estradiol analogs & derivatives, Estradiol pharmacology, Estrogen Receptor Antagonists pharmacology, Female, Fulvestrant, Gene Expression Profiling methods, Gene Expression Regulation, Neoplastic, Genome-Wide Association Study, Humans, Kaplan-Meier Estimate, MCF-7 Cells, Oligonucleotide Array Sequence Analysis, Prognosis, Promoter Regions, Genetic, Protein Binding, RNA Interference, Receptor, ErbB-2 genetics, Receptor, ErbB-2 metabolism, Receptors, Estrogen genetics, Time Factors, Transfection, alpha 1-Antitrypsin genetics, Biomarkers, Tumor metabolism, Breast Neoplasms enzymology, Receptors, Estrogen metabolism, alpha 1-Antitrypsin biosynthesis
- Abstract
Of all breast cancer patients, about 70% are ER+ and 10% are ER+/HER2+. The ER+/HER2+ patients have a worse outcome compared to ER+/HER2- patients. Currently there is a lack of effective prognosis biomarkers for the prediction of outcome in ER+/HER2+ patients. Genome-wide differences in ER binding between the endocrine-responsive and endocrine-resistant cells were discovered using ChIP-seq, and combined with gene expression microarray data to identify direct ER target genes. These genes were correlated to survival outcome using publicly available breast cancer patient cohorts. We found the expression of the gene SERPINA1 to have a significant predictive value for the overall survival (OS) of ER+ patients in the TCGA cohort, and validated this finding in the Curtis cohort. SERPINA1 also has a significant predictive value for the OS of ER+/HER2+ patients in the TCGA cohort, with validation in the Bild cohort. The expression of SERPINA1 can be suppressed by fulvestrant and HER2 siRNA. Our results indicate that ER is constitutively activated, resulting in an E2-independent ER binding to the SERPINA1 gene and upregulation of SERPINA1 expression. Importantly, results of survival correlation suggests that high expression of SERPINA1 could be predictive for a better clinical outcome of ER+ and ER+/HER2+ patients.
- Published
- 2015
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