Phosphorylation of estrogen receptor α serine 167 is predictive of response to endocrine therapy and increases postrelapse survival in metastatic breast cancer

Introduction Endocrine therapy is the most important treatment option for women with hormone-receptor-positive breast cancer. The potential mechanisms for endocrine resistance involve estrogen receptor (ER)-coregulatory proteins and crosstalk between ER and other growth factor signaling networks. However, the factors and pathways responsible for endocrine resistance are still poorly identified. Methods Using immunohistochemical techniques, we focused on the expression and phosphorylation of hormone receptors themselves and examined the phosphorylation of ER-alpha Ser118 and ER-alpha Ser167 and the expression of ER-alpha, ER-beta 1, ER-beta cx/ beta 2, progesterone receptor ( PR), PRA, and PRB in the primary breast carcinomas of 75 patients with metastatic breast cancer who received first-line treatment with endocrine therapy after relapse. Results Phosphorylation of ER-alpha Ser118, but not Ser167, was positively associated with overexpression of HER2, and HER2-positive tumors showed resistance to endocrine therapy. The present study has shown for the first time that phosphorylation of ER-alpha Ser167, but not Ser118, and expression of PRA and PRB, as well as ER-alpha and PR in primary breast tumors are predictive of response to endocrine therapy, whereas expression of ER-beta 1 and ER-beta cx/beta 2 did not affect response to the therapy. In addition, patients with either high phosphorylation of ER-alpha Ser167, or high expression of ER-alpha, PR, PRA, or PRB had a significantly longer survival after relapse. Conclusion These data suggest that phosphorylation of ER-alpha Ser167 is helpful in selecting patients who may benefit from endocrine therapy and is a prognostic marker in metastatic breast cancer.