Coordinate regulation of estrogen-mediated fibronectin matrix assembly and epidermal growth factor receptor transactivation by the G protein-coupled receptor, GPR30.

Estrogen promotes changes in cytoskeletal architecture not easily attributed to the biological action of estrogen receptors, ERalpha and ERbeta. The Gs protein-coupled transmembrane receptor, GPR30, is linked to specific estrogen binding and rapid estrogen-mediated release of heparin-bound epidermal growth factor. Using marker rescue and dominant interfering mutant strategies, we show that estrogen action via GPR30 promotes fibronectin (FN) matrix assembly by human breast cancer cells.

p66 Shc tumor levels show a strong prognostic correlation with disease outcome in stage IIA colon cancer.

Purpose: Most stage IIA colon cancer patients receive no adjuvant therapy despite an estimated 15% risk of disease-related death within 5 years of resection. Prognostication of disease outcome would benefit the clinician by categorizing patients with stage IIA disease by risk. The abundance of the signal transduction proteins p66 Shc and tyrosine-phosphorylated (PY)-Shc in tumor cells is a prognostic indicator of disease outcome in breast cancer, suggesting that Shc analysis may provide prognostic information in stage IIA colon cancer.

p66 Shc and tyrosine-phosphorylated Shc in primary breast tumors identify patients likely to relapse despite tamoxifen therapy.

Introduction: Shc adapter proteins are secondary messenger proteins involved in various cellular pathways, including those mediating receptor tyrosine kinase signaling and apoptosis in response to stress. We have previously reported that high levels of tyrosine-phosphorylated Shc (PY-Shc) and low levels of its inhibitory p66 Shc isoform are strongly prognostic for identifying both early node-negative and more advanced, node-positive, primary breast cancers with high risk for recurrence. Because aberrant activation of tyrosine kinases upstream of Shc signaling proteins has been implicated in resistance to tamoxifen--the most widely prescribed drug for treatment of estrogen receptor-positive breast cancer--we hypothesized that Shc isoforms may identify patients at increased risk of relapsing despite tamoxifen treatment.

Shc proteins are strong, independent prognostic markers for both node-negative and node-positive primary breast cancer.

Activated Shc signaling proteins are implicated in many pathways associated with aggressive disease, and many breast cancer cell lines derived from highly aggressive tumors contain high levels of activated, tyrosine phosphorylated (PY)-Shc (the M(r) 46000 and M(r) 52000 isoforms) relative to levels of an inhibitory M(r) 66000 Shc isoform. It was, therefore, hypothesized that high amounts of PY-Shc relative to the M(r) 66000 Shc isoform would serve as a marker for aggressive neoplasms. Semiquantitative immunohistochemical analyses of PY-Shc and p66 Shc were performed on archival primary breast tumor specimens from 116 women, 17 of whom experienced relapse (6.

Estrogen action via the G protein-coupled receptor, GPR30: stimulation of adenylyl cyclase and cAMP-mediated attenuation of the epidermal growth factor receptor-to-MAPK signaling axis.

Estrogen triggers rapid yet transient activation of the MAPKs, extracellular signal-regulated kinase (Erk)-1 and Erk-2. We have reported that this estrogen action requires the G protein-coupled receptor, GPR30, and occurs via Gbetagamma-subunit protein-dependent transactivation of the epidermal growth factor (EGF) receptor through the release of pro-heparan-bound EGF from the cell surface. Here we investigate the mechanism by which Erk-1/-2 activity is rapidly restored to basal levels after estrogen stimulation.