Hypoxia and ER alpha Transcriptional Crosstalk Is Associated with Endocrine Resistance in Breast Cancer
Abstract
Estrogen receptor-alpha (ER alpha) is the driving transcription factor in 70% of breast cancers and its activity is associated with hormone dependent tumor cell proliferation and survival. Given the recurrence of hormone resistant relapses, understanding the etiological factors fueling resistance is of major clinical interest. Hypoxia, a frequent feature of the solid tumor microenvironment, has been described to promote endocrine resistance by triggering ER alpha down-regulation in both in vitro and in vivo models. Yet, the consequences of hypoxia on ER alpha genomic activity remain largely elusive. In the present study, transcriptomic analysis shows that hypoxia regulates a fraction of ER alpha target genes, underlying an important regulatory overlap between hypoxic and estrogenic signaling. This gene expression reprogramming is associated with a massive reorganization of ER alpha cistrome, highlighted by a massive loss of ER alpha binding sites. Profiling of enhancer acetylation revealed a hormone independent enhancer activation at the vicinity of genes harboring hypoxia inducible factor (HIF alpha) binding sites, the major transcription factors governing hypoxic adaptation. This activation counterbalances the loss of ER alpha and sustains hormone-independent gene expression. We describe hypoxia in luminal ER alpha (+) breast cancer as a key factor interfering with endocrine therapies, associated with poor clinical prognosis in breast cancer patients.
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