Endocrine Abstracts

The estrogen receptor (ER) plays an important role in breast cancer development and progression. Hypoxia was shown to modulate the level of ERα expression and induce ligand-independent transcriptional activation of ERα, which may be intimately associated with the biology of breast carcinomas. Given that phosphorylation affects the transcriptional activity and stabilization of ERα, we examined the changes in phosphorylation of ERα under hypoxic conditions. Hypoxia induced phosphorylation of ERα at serine residues 118 and 167 in the absence of estrogen. Phosphorylation-defective ERα mutants with serine-to-alanine replacements at residues 118 and 167 had impaired hypoxia-induced ERα activation, showing that serine residues 118 and 167 are involved in hypoxia-induced ERα activation. The hypoxia-induced ERα-mediated transcriptional response was dependent on both the ERK1/2 MAPK and PI3K pathways, but not the p38 pathway, as assessed using chemical inhibitors. Both the A/B and DEF domains of ERα were activated by hypoxia, indicating that both the N- and C-termini are involved in activation. These data show that ERα phosphorylation via both the MAPK and PI3K pathways is one mechanism leading to ERα activation under hypoxia.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This work was supported however funding details unavailable.