title: Prognostic impact of total and tyrosine phosphorylated GIV/Girdin in breast cancers.
abstract: Gα-interacting vesicle-associated protein (GIV, aka Girdin) is a guanine exchange factor (GEF) for the trimeric G protein Gαi and a bona fide metastasis-related gene that serves as a platform for amplification of tyrosine-based 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 and P = 0.0048 in late clinical stages). Activated pYGIV in the cytoplasm had the greatest prognostic impact in late clinical stages (P = 0.006). Furthermore, we found that the prognostic 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) but not in triple-negative breast cancers. In triple-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 correlation with 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.-Dunkel, Y., Diao, K., Aznar, N., Swanson, L., Liu, L., Zhu, W., Mi, X.-Y., Ghosh, P. Prognostic impact of total and tyrosine phosphorylated GIV/Girdin in breast cancers.
authors.affiliation: Department of Medicine.|Department of Cell and Molecular Medicine.
authors.forename: Ying
authors.initials: Y
authors.lastname: Dunkel
authors.affiliation: Department of Pathology, China Medical University, Shenyang, China.
authors.forename: Kexin
authors.initials: K
authors.lastname: Diao
authors.affiliation: Department of Medicine.|Department of Cell and Molecular Medicine.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Aznar
authors.affiliation: Department of Medicine.|Department of Cell and Molecular Medicine.
authors.forename: Lee
authors.initials: L
authors.lastname: Swanson
authors.affiliation: Department of Medicine.|Department of Cell and Molecular Medicine.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Liu
authors.affiliation: Division of Biomedical Informatics, University of California, San Diego, La Jolla, California, USA.
authors.forename: Wenhong
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Department of Pathology, China Medical University, Shenyang, China; mixiaoyi2005@163.com.
authors.forename: Xiao-Yi
authors.initials: XY
authors.lastname: Mi
authors.affiliation: Department of Medicine, prghosh@ucsd.edu.|Department of Cell and Molecular Medicine.
authors.forename: Pradipta
authors.initials: P
authors.lastname: Ghosh
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000175:diagnosis / Q000453:epidemiology / Q000378:metabolism* / Q000473:pathology; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006801:Humans; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D010766:Phosphorylation; D011379:Prognosis; D015398:Signal Transduction / Q000235:genetics; D014443:Tyrosine / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
chemical_list: C502451:CCDC88A protein, human; D020662:Guanine Nucleotide Exchange Factors; D008840:Microfilament Proteins; D033921:Vesicular Transport Proteins; D014443:Tyrosine; D019204:GTP-Binding Proteins
keywords: HER-2/neu; guanidine exchange factor; prognostication biomarker; survival analysis; triple negative