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

Abstract

To determine the relationship of the multiple sites of oestrogen receptor α (ERα) 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 ERα, p-S104/106-ERα, p-S118-ERα, p-S167-ERα, p-S282-ERα, p-S294-ERα, p-T311-ERα and p-S559-ERα. Relationships of phosphorylated ERα 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-ERα were significantly associated with reduced overall survival (OS). Along with tumour size and node status, a novel phosphorylation score (P7 score ≥3), taking into account all seven p-ERα 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 P7 score (≥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 ERα is the site at which integration of diverse signals occurs to regulate breast cancer growth and survival, the ERα 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. © 2010 Society for Endocrinology.