Phosphorylation of Estrogen Receptor β at Serine 105 Is Associated with Good Prognosis in Breast Cancer

Estrogen receptor (ER) action is modulated by posttranslational modifications. Although ERα phosphorylation correlates with patient outcome, ERβ is similarly phosphorylated but its significance in breast cancer has not been addressed. We investigated whether ERβ that is phosphorylated at serine 105 (S105-ERβ) is expressed in breast cancer and assessed potential clinical implications of this phosphorylation. Following antibody validation, S105-ERβ expression was studied in tissue microarrays comprising 108 tamoxifen-resistant and 351 tamoxifen-sensitive cases and analyzed against clinical data. S105-ERβ regulation in vitro was assessed by Western blot, flow cytometry, and immunofluorescence. Nuclear S105-ERβ was observed in breast carcinoma and was associated with better survival (Allred score ≥3), even in tamoxifen-resistant cases, and additionally correlated with ERβ1 and ERβ2 expression. Distinct S105-ERβ nuclear speckles were seen in some higher grade tumors. S105-ERβ levels increased in MCF-7 cells in response to 17β-estradiol, the ERβ-specific agonist diarylpropionitrile, and the partial ERβ-agonist genistein. S105-ERβ nuclear speckles were also seen in MCF-7 cells and markedly increased in size and number at 24 hours following 17β-estradiol and, in particular diarylpropionitrile, treatment. These speckles were coexpressed with ERβ1 and ERβ2. Presence of S105-ERβ in breast cancer and association with improved survival, even in endocrine resistant breast tumors suggest S105-ERβ might be a useful additional prognostic marker in this disease.