Phosphorylation of estrogen receptor-alpha at Ser167 is indicative of longer disease-free and overall survival in breast cancer patients.
OBJECTIVE
Ser(167) was first identified as a major phosphorylation site of the estrogen receptor -alpha (ER) positive in the MCF7 breast cancer cell line. Subsequent studies have shown that Ser(167) phosphorylation is important in the regulation of ER activity and have identified p90RSK and AKT as protein kinases that phosphorylate Ser(167). The purpose of this study was to determine the importance of Ser(167) phosphorylation in breast cancer progression.


METHODS
Immunohistochemical staining of primary breast cancer biopsies (n = 290) was carried out using antibodies specific for ER phosphorylated at Ser(167) and for phosphorylated p44/p42 mitogen-activated protein kinase (MAPK), phosphorylated p90RSK, and phosphorylated AKT.


RESULTS
In ER-positive breast cancer patients, Ser(167) phosphorylation was associated with low tumor grade (P = 0.011), lymph node negativity (P = 0.034), and relapse-free (P = 0.006) and overall (P = 0.023) survival. Further, Ser(167) phosphorylation was strongly associated with phosphorylated p90RSK (P < 0.001), previously shown to phosphorylate Ser(167) in vitro, as well as being associated with phosphorylated MAPK (P < 0.0005). The activities of both kinases also seemed to be indicative of better prognosis. There was, however, no association between HER2 positivity and Ser(167) phosphorylation nor were the activities of MAPK or p90RSK associated with HER2 status, suggesting that other cell surface receptors may be important in regulating these activities in breast cancer.


CONCLUSIONS
These findings show that phosphorylation at Ser(167) of ER predicts for likelihood of response of ER-positive breast cancer patients to endocrine therapies.
Jiang
Jie
J
Cancer Research UK Laboratories, Department of Oncology, Imperial College London, London, United Kingdom.
Sarwar
Naveed
N
Peston
David
D
Kulinskaya
Elena
E
Shousha
Sami
S
Coombes
R Charles
RC
Ali
Simak
S
D001943:Breast Neoplasms / Q000378:metabolism* / Q000401:mortality*; D045744:Cell Line, Tumor; D018450:Disease Progression; D018572:Disease-Free Survival; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D010766:Phosphorylation; D011379:Prognosis; D011960:Receptors, Estrogen / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D012694:Serine / Q000737:chemistry*; D013997:Time Factors; D016896:Treatment Outcome
D047628:Estrogen Receptor alpha; D011960:Receptors, Estrogen; D012694:Serine; D038744:Ribosomal Protein S6 Kinases, 90-kDa