title: Phosphorylation of estrogen receptor alpha serine 167 is predictive of response to endocrine therapy and increases postrelapse survival in metastatic breast cancer.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Oncology and Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. hirokoy@med.nagoya-cu.ac.jp
authors.forename: Hiroko
authors.initials: H
authors.lastname: Yamashita
authors.forename: Mariko
authors.initials: M
authors.lastname: Nishio
authors.forename: Shunzo
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Ando
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sugiura
authors.forename: Zhenhuan
authors.initials: Z
authors.lastname: Zhang
authors.forename: Maho
authors.initials: M
authors.lastname: Hamaguchi
authors.forename: Keiko
authors.initials: K
authors.lastname: Mita
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Fujii
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Iwase
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D019556:COS Cells; D002522:Chlorocebus aethiops; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism*; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D012008:Recurrence; D016019:Survival Analysis; D014162:Transfection
chemical_list: D018931:Antineoplastic Agents, Hormonal; D004815:Epidermal Growth Factor; D004958:Estradiol; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D010768:Phosphoserine; D018719:Erb-b2 Receptor Tyrosine Kinases; D011980:Receptors, Progesterone; D011994:Recombinant Proteins