Association of ErbB2 Ser1113 phosphorylation with epidermal growth factor receptor co-expression and poor prognosis in human breast cancer.
The carboxyterminal domain of the epidermal growth factor receptor (EGFR)--a putative binding site for the ubiquitin ligase Cbl--is the site of serine phosphorylation events which are essential for ligand-dependent EGFR desensitization and degradation. Using a monoclonal antibody (aPS1113) which selectively recognizes the homologous phosphorylated domain in the ErbB2 oncoprotein, we show here that wild-type ErbB2 becomes Ser1113-phosphorylated following treatment of 3T3 cells with growth factors or tyrosine phosphatase inhibitors. In EGFR-overexpressing A431 cells, ligand-inducible aPS1113 immunoreactivity declines more rapidly than other detectable phosphorylation events and is followed by EGFR downregulation. Analysis of 65 ErbB2-expressing primary breast cancers reveals a highly significant relationship between Ser1113 phosphorylation and EGFR overexpression (p < 0.0001) as well as an association with poor prognosis (p = 0.005). We submit that ErbB2 Ser1113 phosphorylation status represents a novel and informative biomarker of cancer cell biology and tumor behavior.
Ouyang
X
X
Department of Metabolic Medicine, Imperial College School of Medicine, London, UK.
Gulliford
T
T
Zhang
H
H
Smith
G
G
Huang
G
G
Epstein
R J
RJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000077214:Becaplermin; D001943:Breast Neoplasms / Q000378:metabolism* / Q000401:mortality; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D018613:Microscopy, Confocal; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D010766:Phosphorylation; D010768:Phosphoserine; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011379:Prognosis; D020574:Proto-Oncogene Proteins c-sis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology / Q000378:metabolism*; D014162:Transfection; D014638:Vanadates / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D000077214:Becaplermin; D005576:Colforsin; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D015240:Phorbol 12,13-Dibutyrate; D010768:Phosphoserine; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D018719:Erb-b2 Receptor Tyrosine Kinases; D014638:Vanadates