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

Journal article

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

Authors: Yang, J; AlTahan, A; Jones, D; Buffa, F; Bridges, E

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: National Academy of Sciences
• Journal: Proceedings of the National Academy of Sciences of the United States of America
• Volume: 112
• Issue: 49
• Pages: 15172-15177
• Publication date: 2015-12-01
• DOI: 10.1073/pnas.1422015112
• EISSN: 1091-6490
• ISSN: 0027-8424
• Language: English
• Keywords: tamoxifen; ERα; HIF-1α