Estrogen receptor-α directly regulates the hypoxia-inducible factor 1 pathway associated with antiestrogen response in breast cancer

A majority of breast cancers are driven by estrogen via estrogen receptor-alpha (ERa). Our previous studies indicate that hypoxia-inducible factor 1 alpha (HIF-1 alpha) cooperates with ERa in breast cancer cells. However, whether ERa is implicated in the direct regulation of HIF-1 alpha and the role of HIF-1 alpha in endocrine therapy response are unknown. In this study we found that a subpopulation of HIF-1 alpha targets, many of them bearing both hypoxia response elements and estrogen response elements, are regulated by ERa in normoxia and hypoxia. Interestingly, the HIF-1 alpha gene itself also bears an estrogen response element, and its expression is directly regulated by ER alpha. Clinical data revealed that expression of the HIF-1 alpha gene or a hypoxia metagene signature is associated with a poor outcome to endocrine treatment in ER alpha(+) breast cancer. HIF-1 alpha was able to confer endocrine therapy resistance to ER alpha(+) breast cancer cells. Our findings define, for the first time to our knowledge, a direct regulatory pathway between ER alpha and HIF-1 alpha, which might modulate hormone response in treatment.