Hypoxia and ERα Transcriptional Crosstalk Is Associated with Endocrine Resistance in Breast Cancer

SIMPLE SUMMARY: Hormone receptor positive breast cancer patients are treated with anti-hormone molecules as a standard of care. However, resistance frequently occurs, leading to hormone resistant metastatic relapses in foreign organs. Understanding the molecular mechanisms through which breast cancer cells evade therapeutic pressure is of paramount interest. Hypoxia, which refers to oxygen deprivation and is characterized by the activation of hypoxia inducible factors, is a common feature of the solid tumor microenvironment, yet its influence on estrogen receptor alpha activity remains elusive. Here, we investigate the consequence of hypoxia and the signaling of hypoxia inducible factors on hormone responsiveness in breast cancer cells and its clinical implications. ABSTRACT: Estrogen receptor-alpha (ERα) 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 ERα down-regulation in both in vitro and in vivo models. Yet, the consequences of hypoxia on ERα genomic activity remain largely elusive. In the present study, transcriptomic analysis shows that hypoxia regulates a fraction of ERα target genes, underlying an important regulatory overlap between hypoxic and estrogenic signaling. This gene expression reprogramming is associated with a massive reorganization of ERα cistrome, highlighted by a massive loss of ERα binding sites. Profiling of enhancer acetylation revealed a hormone independent enhancer activation at the vicinity of genes harboring hypoxia inducible factor (HIFα) binding sites, the major transcription factors governing hypoxic adaptation. This activation counterbalances the loss of ERα and sustains hormone-independent gene expression. We describe hypoxia in luminal ERα (+) breast cancer as a key factor interfering with endocrine therapies, associated with poor clinical prognosis in breast cancer patients.