Overexpression of activated phospholipase Cgamma1 is a risk factor for distant metastases in T1-T2, N0 breast cancer patients undergoing adjuvant chemotherapy

Phospholipase Cgamma1 (PLCgamma1) is highly expressed in several tumors. We have previously reported that both stable and inducible PLCgamma1 down-regulation resulted in an almost complete inhibition of breast cancer-derived experimental lung metastasis formation. The aim of our study is to evaluate the association between the expression of PLCgamma1 and of PLCgamma1 phosphorylated at Tyr1253 (PLCgamma1-pY1253) and at Tyr783 (PLCgamma1-pY783) with the clinical outcome of patients with node negative, T1/T2 breast cancers. The study groups consisted of 292 (training set) and 122 (validation set) patients presenting with primary unilateral breast carcinoma (T1-T2), with no evidence of nodal involvement and distant metastases. PLCgamma1, PLCgamma1-pY1253 and PLCgamma1-pY783 protein expression were assessed by immunohistochemistry on tissue microarrays and the results correlated with the clinical data using Kaplan–Meier curves and multivariate Cox regression analysis. Tumor cells while expressing variable proportions of cytoplasmic PLCgamma1, express PLCgamma1-pY1253 and PLCgamma1-pY783 predominantly in the nucleus. High expression of PLCgamma1, and of its activated forms, is associated with a worse clinical outcome in terms of incidence of distant metastases, and not of local relapse in T1-T2, N0 breast cancer patients undergone adjuvant chemotherapy. PLCgamma1 over-expression appears to be a reliable predictive surrogate marker of development of metastases. Thus, targeting PLCgamma1 pathways might represent a potential therapeutic approach for the prevention of metastatic disease in breast cancer.