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

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

SUBMITTER: Yang J 

PROVIDER: S-EPMC4679044 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature