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 ER alpha phosphorylation correlates with patient outcome, ER beta is similarly phosphorylated but its significance in breast cancer has not been addressed. We investigated whether ER beta that is phosphorylated at serine 105 (S105-ER beta) is expressed in breast cancer and assessed potential clinical implications of this phosphorylation. Following antibody validation, S105-ER beta expression was studied in tissue microarrays comprising 108 tamoxifen-resistant and 351 tamoxilen-sensitive cases and analyzed against clinical data. S105-ER beta regulation in vitro was assessed by Western blot, flow cytometry, and immunofluorescence. Nuclear S105-ER beta was observed in breast carcinoma and was associated with better survival (Allred score even in tamoxifen-resistant cases, and additionally correlated with ER beta 1 and ER beta 2 expression. Distinct S105-ER beta nuclear speckles were seen in some higher grade tumors. S105-ER beta levels increased in MCF-7 cells in response to 17 beta-estradiol, the ER beta-specific agonist diarylpropionitrile, and the partial ER beta-agonist genistein. S105-ER beta nuclear speckles were also seen in MCF-7 cells and markedly increased in size and number at 24 hours following 17 beta-estradiol and, in particular diarylpt opionitrile, treatment. These speckles were co-expressed with ER beta 1 and ER beta 2. Presence of s105-ER beta in bream cancer and association with improved survival, even in endocrine resistant breast tumors suggest S105-ER beta might be a useful additional prognostic marker in this disease. (Am J Pathol 2010, 177:1079-1086: DOI: 10.2353/ajpath.2010.090886)