Distinct ErbB-2-coupled signaling pathways promote mammary tumors with unique pathologic and transcriptional profiles

Babette Schade, Sonya H.L. Lam, Daniela Cernea, Virginie Sanguin-Gendreau, Robert Cardiff, Boonim L. Jung, Michael Hallett, William J. Muller

Research output: Contribution to journalArticle

19 Scopus citations

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-1α, 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.

Original languageEnglish (US)
Pages (from-to)7579-7588
Number of pages10
JournalCancer Research
Volume67
Issue number16
DOIs
StatePublished - Aug 15 2007

    Fingerprint

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Schade, B., Lam, S. H. L., Cernea, D., Sanguin-Gendreau, V., Cardiff, R., Jung, B. L., Hallett, M., & Muller, W. J. (2007). Distinct ErbB-2-coupled signaling pathways promote mammary tumors with unique pathologic and transcriptional profiles. Cancer Research, 67(16), 7579-7588. https://doi.org/10.1158/0008-5472.CAN-06-4724