Distinct ErbB-2-coupled signalling pathways promote mammary tumors with unique pathological and transcriptional profiles

ABSTRACT: ErbB-2 overexpression and amplification occurs in 15 - 30% of human invasive breast carcinomas associated with poor clinical prognosis. Previously, we have demonstrated 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 Grb2 (Neu-YB) and Shc (Neu-YD) binding sites can induce mammary tumourigenesis and metastasis. Here we show that Neu-YC and Neu-YE transgenic mice develop metastatic mammary tumours. A detailed comparison of pathological and transcriptional profiles among all Neu mutant mouse models revealed that Neu-YC, -YD and -YE mammary tumours shared similar pathological and transcriptional features correlating with their capacity to signal through a common adaptor like Shc. In contrast, the Neu-YB mouse model displayed a unique pathology with a high metastatic potential that correlates with a distinct transcriptional profile. We identified genes specifically expressed in YB-induced mammary tumours, including CXCL12/SDF-1α that promotes malignant tumour progression. Furthermore, Neu-YB tumour epithelial cells showed abundant intracellular CXCL12/SDF-1α protein, which may reflect the more aggressive phenotype among all Neu mutant mouse models. These findings indicate that activation of distinct Neu-coupled signalling pathways has a deep impact on the biological behaviour of Neu-induced tumours. Keywords: genetic modification, Neu mutant mouse models, mammary tumor

ORGANISM(S): Mus musculus

PROVIDER: GSE7595 | GEO | 2007/08/15

SECONDARY ACCESSION(S): PRJNA100181

REPOSITORIES: GEO