A phosphorylation code for oestrogen receptor-alpha predicts clinical outcome to endocrine therapy in breast cancer

To determine the relationship of the multiple sites of oestrogen receptor alpha (ERalpha) phosphorylation to clinical outcome after tamoxifen therapy, sections from tissue microarrays representing over 300 ER+ breast cancers from patients who were treated with surgery+radiation and then tamoxifen were used for immunohistochemical determination of total ERalpha, p-S104/106-ERalpha, p-S118-ERalpha, p-S167-ERalpha, p-S282-ERalpha, p-S294-ERalpha, p-T311-ERalpha and p-S559-ERalpha. Relationships of phosphorylated ERalpha to overall and relapse-free survival (RFS; breast cancer death or recurrence) were tested using single (univariate) and multiple (multivariate) predictor statistical models. Large tumour size, node positivity, high grade, progesterone receptor (PR) negative status and low levels of p-S282-ERalpha were significantly associated with reduced overall survival (OS). Along with tumour size and node status, a novel phosphorylation score (P(7) score > or = 3), taking into account all seven p-ERalpha sites, was significantly associated with reduced OS in univariate and multivariate analyses (hazard ratio (HR)=2.24, 95% confidence interval (CI) 1.15-4.34, n=335; P=0.018). Along with tumour size, node status, grade and PR status, a high P(7) score (> or = 3) was significantly associated with reduced RFS in univariate and multivariate analyses (HR=1.71, 95% CI 1.03-2.86, n=332; P=0.039). Since ERalpha is the site at which integration of diverse signals occurs to regulate breast cancer growth and survival, the ERalpha phosphorylation score may be a surrogate marker of the balance between oestrogen-dependent and crosstalk-dependent receptor activity, and is potentially a prognostic marker of clinical outcome in a tamoxifen-treated population of patients.