Prognostic impact of total and tyrosine phosphorylated GIV/Girdin in breast cancers

Abstract

Ga-interacting vesicle-Associated protein (GIV, aka Girdin) is a guanine exchange factor (GEF) for the trimericGproteinGai anda bona fidemetastasis-related gene that serves as a platform for amplification of tyrosinebased signals via G-protein intermediates. Here we present the first exploratory biomarker study conducted on a cohort of 187 patients with breast cancer to evaluate the prognostic role of total GIV (tGIV) and tyrosine phosphorylated GIV (pYGIV) across the various molecular subtypes. A Kaplan-Meier analysis of recurrence-free survival showed that the presence of tGIV, either cytoplasmic or nuclear, carried poor prognosis, but that nuclear tGIV had a greater prognostic impact (P = 0.007 in early andP=0.0048 in late clinical stages). Activated pYGIV in the cytoplasm hadthe greatest prognosticimpact inlate clinical stages (P=0.006). Furthermore,wefound that theprognostic impacts of cytoplasmic pYGIV and nuclear tGIV were additive (hazard ratio 19.0548; P = 0.0002). Surprisingly, this additive effect of nuclear tGIV/cytoplasmic pYGIV was observed in human epidermal growth factor receptor 2-positive tumors (hazard ratio 16.918;P=0.0005)butnot in triple-negativebreast cancers. Intriple-negative breast cancers,tGIV and cytoplasmic pYGIV had no prognostic impact; however, membrane-Association of pYGIV carried a poor prognosis (P= 0.026). Both tGIV and pYGIV showed no correlationwith clinical stage, tumor size, pathologic type, lymph node involvement, and BRCA1/2 status.We conclude that immunocytochemical detection of pYGIV and tGIV can serve as an effective prognosticator. On the basis of the differential prognostic impact of tGIV/pYGIV within each molecular subtype, we propose a diagnostic algorithm. Further studies on larger cohorts are essential to rigorously assess the effectiveness and robustness of this algorithm in prognosticating outcome among patients with breast cancer.