SERPINA1 is a direct estrogen receptor target gene and a predictor of survival in breast cancer patients
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Hei Jason Chan1, Haiqing Li2, Zheng Liu3, Yate-Ching Yuan3, Joanne Mortimer4, Shiuan Chen1
1Department of Cancer Biology, Beckman Research Institute of the City of Hope, Duarte, California, USA
2Department of Molecular Medicine, Beckman Research Institute of the City of Hope, Duarte, California, USA
3Bioinformatics Core Facility, Beckman Research Institute of the City of Hope, Duarte, California, USA
4Department of Medical Oncology, Beckman Research Institute of the City of Hope, Duarte, California, USA
Shiuan Chen, e-mail: [email protected]
Keywords: estrogen receptor, breast cancer, endocrine resistance, SERPINA1, survival analysis
Received: December 19, 2014 Accepted: June 19, 2015 Published: June 29, 2015
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.
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