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

Breast Cancer Res. 2005;7(5):R753-64. doi: 10.1186/bcr1285. Epub 2005 Jul 27.


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-beta1, ER-betacx/beta2, 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-beta1 and ER-betacx/beta2 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antineoplastic Agents, Hormonal / therapeutic use*
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / mortality
  • Breast Neoplasms / pathology*
  • COS Cells
  • Chlorocebus aethiops
  • Epidermal Growth Factor / pharmacology
  • Estradiol / pharmacology
  • Estrogen Receptor alpha / genetics*
  • Estrogen Receptor alpha / metabolism*
  • Estrogen Receptor beta / genetics
  • Estrogen Receptor beta / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Neoplasm Metastasis
  • Phosphorylation
  • Phosphoserine / metabolism*
  • Prognosis
  • Receptor, ErbB-2 / genetics
  • Receptors, Progesterone / genetics
  • Receptors, Progesterone / metabolism
  • Recombinant Proteins / pharmacology
  • Recurrence
  • Survival Analysis
  • Transfection


  • Antineoplastic Agents, Hormonal
  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • Receptors, Progesterone
  • Recombinant Proteins
  • Phosphoserine
  • Estradiol
  • Epidermal Growth Factor
  • Receptor, ErbB-2