Hypoxia induced phosphorylation of estrogen receptor at serine 118 in the absence of ligand

• Published in: The Journal of steroid biochemistry and molecular biology Vol. 174; pp. 146 - 152
• Main Authors: Park, Joonwoo, Lee, YoungJoo
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.11.2017; Elsevier BV
• Subjects: Breast cancer; Breast carcinoma; Cell Line, Tumor; Cell Movement; Cell Proliferation; Endocrine therapy; Estrogen receptor; Estrogen Receptor alpha - genetics; Estrogen Receptor alpha - metabolism; Estrogen receptors; Estrogens; Extracellular signal-regulated kinase; HEK293 Cells; Humans; Hypoxia; Hypoxia - metabolism; Ligands; MAP kinase; Mitogen-Activated Protein Kinases - metabolism; Phosphorylation; Protein kinase; Serine; Serine - metabolism; Transcription activation; Estrogen receptor; Hypoxia; Phosphorylation
• ISSN: 0960-0760; 1879-1220
• DOI: 10.1016/j.jsbmb.2017.08.013

•ERα Ser118 is phosphorylated by ERK under hypoxia in the absence of estrogen.•ERα activation and degradation under hypoxia is independent of S118 phosphorylation.•Inhibition of ERα S118 phosphorylation decreases cell proliferation and migration under hypoxia. The estrogen receptor (ER) plays an important role in breast cancer development and progression. Hypoxia modulates the level of ERα expression and induces ligand-independent transcriptional activation of ERα, which is closely related with the biology of breast carcinomas. Since phosphorylation itself affects the transcriptional activity and stabilization of ERα, we examined changes in ERα phosphorylation under hypoxic conditions. Hypoxia induced phosphorylation of ERα at serine residue 118 (S118) in the absence of estrogen through the mitogen-activated protein kinase (MAPK)/ERK1/2 pathway. Cell proliferation was significantly decreased under normoxia or hypoxia when ERα harboring the S118A mutation was overexpressed. Our previous studies showed that ER degradation is the most prominent phenomenon under hypoxia. E2-induced ER protein downregulation is dependent on phosphorylation of S118. However, hypoxia-induced ERα degradation did not involve S118 phosphorylation. Our study implies the existence of a differential mechanism between E2 and hypoxia-mediated ERα protein degradation. Understanding the mechanistic behavior of ER under hypoxia will likely facilitate understanding of endocrine therapy resistance and development of treatment strategies for breast cancer.