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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.

Original publication

DOI

10.1073/pnas.1422015112

Type

Journal article

Journal

Proc Natl Acad Sci U S A

Publication Date

08/12/2015

Volume

112

Pages

15172 - 15177

Keywords

ERα, HIF-1α, tamoxifen, Breast Neoplasms, Drug Resistance, Neoplasm, Estrogen Receptor Modulators, Estrogen Receptor alpha, Female, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Signal Transduction, Tamoxifen, Transcription, Genetic