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.
Highlights
The estrogen receptor α (ER) is a crucial tran scription factor that is required for cell proliferation in the majority of breast cancer cases, which accounts for about 70% of all breast cancers
The ER binding sites were annotated with the genes, and we plotted the number of binding sites against the distance to the closest transcription start sites (TSS)
Comparison of the number of ER binding sites close to the TSS demonstrated that the distribution of the number of binding sites in the LTEDaro DMSO was comparable to that found in the MCF7aro E2 (Figure 1A)
Summary
The estrogen receptor α (ER) is a crucial tran scription factor that is required for cell proliferation in the majority of breast cancer cases, which accounts for about 70% of all breast cancers. A major treatment of ER+ breast cancer is endocrine therapy using anti-estrogens like tamoxifen or aromatase inhibitors (AIs). To investigate the molecular action of AIs, our laboratory has generated an aromatase-overexpressing MCF-7 cell line, i.e., MCF-7aro [3]. For this project, we used MCF7aro cells as a model for endocrine-responsive breast cancer, and Long Term Estrogen Deprived (LTEDaro) cells as a model for endocrine-resistant breast cancer [4]. In the endocrine-resistant cells, the ER can be activated by other mechanisms such as phosphorylation, so even in the absence of E2, the ER is able to bind to chromatin and www.impactjournals.com/oncotarget activate target genes. The goal of this study is to find such ER binding sites and target genes which will improve our understanding of the roles of ER in both endocrineresponsive and resistant cancers
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