Abstract
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.
DOI
10.1073/pnas.1422015112
Publication Date
2015-12-08
Publication Title
Proceedings of the National Academy of Sciences
Volume
112
Issue
49
Publisher
Proceedings of the National Academy of Sciences
ISSN
1091-6490
Embargo Period
2024-11-19
First Page
15172
Last Page
15177
Recommended Citation
Yang, J., AlTahan, A., Jones, D., Buffa, F., & et al. (2015) 'Estrogen receptor-α directly regulates the hypoxia-inducible factor 1 pathway associated with antiestrogen response in breast cancer', Proceedings of the National Academy of Sciences, 112(49), pp. 15172-15177. Proceedings of the National Academy of Sciences: Available at: https://doi.org/10.1073/pnas.1422015112
