title: Distinct ErbB-2 coupled signaling pathways promote mammary tumors with unique pathologic and transcriptional profiles.
abstract: ErbB-2 overexpression and amplification occurs in 15% to 30% of human invasive breast carcinomas associated with poor clinical prognosis. Previously, we have shown that four ErbB-2/Neu tyrosine-autophosphorylation sites within the cytoplasmic tail of the receptor recruit distinct adaptor proteins and are sufficient to mediate transforming signals in vitro. Two of these sites, representing the growth factor receptor binding protein 2 (Grb2; Neu-YB) and the Src homology and collagen (Shc; Neu-YD) binding sites, can induce mammary tumorigenesis and metastasis. Here, we show that transgenic mice bearing the two other ErbB-2 autophosphorylation sites (Neu-YC and Neu-YE) develop metastatic mammary tumors. A detailed comparison of biological profiles among all Neu mutant mouse models revealed that Neu-YC, Neu-YD, and Neu-YE mammary tumors shared similar pathologic and transcriptional features. By contrast, the Neu-YB mouse model displayed a unique pathology with a high metastatic potential that correlates with a distinct transcriptional profile, including genes that promote malignant tumor progression such as metalloproteinases and chemokines. Furthermore, Neu-YB tumor epithelial cells showed abundant intracellular protein level of the chemokine CXCL12/SDF-1alpha, which may reflect the aggressive nature of this Neu mutant mouse model. Taken together, these findings indicate that activation of distinct Neu-coupled signaling pathways has an important impact on the biological behavior of Neu-induced tumors.
authors: Molecular Oncology Group, McGill University Health Centre, McGill University, Montreal, Quebec, Canada.
authors: Babette
authors: B
authors: Schade
authors: Sonya H L
authors: SH
authors: Lam
authors: Daniela
authors: D
authors: Cernea
authors: Virginie
authors: V
authors: Sanguin-Gendreau
authors: Robert D
authors: RD
authors: Cardiff
authors: Boonim L
authors: BL
authors: Jung
authors: Michael
authors: M
authors: Hallett
authors: William J
authors: WJ
authors: Muller
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000096:biosynthesis / Q000235:genetics; D004789:Enzyme Activation; D051380:GRB2 Adaptor Protein / Q000378:metabolism; D020869:Gene Expression Profiling; D020935:MAP Kinase Signaling System; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014158:Transcription, Genetic
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D051380:GRB2 Adaptor Protein; D019869:Phosphatidylinositol 3-Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; C515255:CXCL12 protein, human; C515256:Cxcl12 protein, mouse; C495949:Grb2 protein, mouse; C528024:SHC1 protein, human; C528034:Shc1 protein, mouse