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Phosphorylation of Estrogen Receptor- at Ser¹⁶⁷ Is Indicative of Longer Disease-Free and Overall Survival in Breast Cancer Patients

Authors' Affiliations: ¹ Cancer Research UK Laboratories, Department of Oncology, ² Department of Histopathology, and ³ Statistical Advisory Service, Imperial College London, London, United Kingdom

Requests for reprints: Simak Ali, Department of Oncology, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, United Kingdom. E-mail: simak.ali{at}imperial.ac.uk.

Purpose: Ser¹⁶⁷ was first identified as a major phosphorylation site of the estrogen receptor - (ER) positive in the MCF7 breast cancer cell line. Subsequent studies have shown that Ser¹⁶⁷ phosphorylation is important in the regulation of ER activity and have identified p90RSK and AKT as protein kinases that phosphorylate Ser¹⁶⁷. The purpose of this study was to determine the importance of Ser¹⁶⁷ phosphorylation in breast cancer progression.

Experimental Design: Immunohistochemical staining of primary breast cancer biopsies (n = 290) was carried out using antibodies specific for ER phosphorylated at Ser¹⁶⁷ and for phosphorylated p44/p42 mitogen-activated protein kinase (MAPK), phosphorylated p90RSK, and phosphorylated AKT.

Results: In ER-positive breast cancer patients, Ser¹⁶⁷ 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, Ser¹⁶⁷ phosphorylation was strongly associated with phosphorylated p90RSK (P < 0.001), previously shown to phosphorylate Ser¹⁶⁷ 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 Ser¹⁶⁷ 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 Ser¹⁶⁷ of ER predicts for likelihood of response of ER-positive breast cancer patients to endocrine therapies.