ShcA signalling is essential for tumour progression in mouse models of human breast cancer

Abstract

To explore the in vivo significance of ShcA during mammary tumorigenesis, we used mice expressing several phosphotyrosine-deficient ShcA alleles under the control of their endogenous promoter. We show that all three ShcA tyrosine phosphorylation sites are involved in the early stages of mammary tumour progression, including loss of the myoepithelial cell layer surrounding hyperplasias and during progression to carcinoma. We have determined that signals emanating from Y313 are important for tumour cell survival, whereas Y239/240 transduce signals promoting tumour vascularization. We further demonstrate that loss of ShcA expression in mammary epithelial cells abrogates tumour development. This study is the first to directly demonstrate that signalling downstream from the ShcA adaptor protein is critical for breast cancer development.

Integrin-linked kinase has a critical role in ErbB2 mammary tumor progression: implications for human breast cancer

“…We have previously shown that the MMTV/NIC strain develops metastatic mammary tumors with comparable latency to other MMTV/activated ErbB2 strains (Ursini- Siegel et al, 2008). Because NIC transgene also co-express Cre recombinase due to the presence of internal ribosome entry site (IRES), mammary epithelial cells expressing activated ErbB2 will excise the conditional ILK allele (Ursini- Siegel et al, 2008). Thus the coupled expression of ErbB2 and Cre recombinase precludes the possibility of obtaining ErbB2-expressing Crenegative 'escapee' populations that could possibly contribute to the tumor.…”

“…We have previously shown that ectopic expression of ILK results in induction of metastatic mammary tumors that possess the hallmarks of an EMT phenotype (White et al, 2001). Using an ErbB2 transgenic model (Ursini- Siegel et al, 2008), we have shown that mammary epithelial disruption of ILK resulted in a dramatic delay in mammary tumor induction. Analyses of premalignant ErbB2-expressing mammary epithelium lacking ILK function has revealed that this block in ErbB2 tumor induction is associated with profound block in epithelial proliferation (Figure 2d, Supplementary Figure S2).…”

“…To determine if ILK expression is required for the induction of mammary tumors in these MMTV/activated ErbB2 transgenic mice (NIC strain), we introduced the conditional ILK alleles into this strain. We have previously shown that the MMTV/NIC strain develops metastatic mammary tumors with comparable latency to other MMTV/activated ErbB2 strains (Ursini- Siegel et al, 2008). Because NIC transgene also co-express Cre recombinase due to the presence of internal ribosome entry site (IRES), mammary epithelial cells expressing activated ErbB2 will excise the conditional ILK allele (Ursini- Siegel et al, 2008).…”

“…Thus the coupled expression of ErbB2 and Cre recombinase precludes the possibility of obtaining ErbB2-expressing Crenegative 'escapee' populations that could possibly contribute to the tumor. Indeed, we successfully showed that this approach results in complete ablation of targeted allele in NIC mice harboring either Stat3 or ShcA conditional alleles (Ursini- Siegel et al, 2008;Ranger et al, 2009).…”

“…To investigate the role of ILK in ErbB2 tumor progression, we have assessed the effect of the targeted disruption of ILK in mammary epithelium on both normal mammary development and ErbB2 tumor progression. To accomplish this, we have interbred mice bearing a conditional ILK allele (Terpstra et al, 2003) to separate transgenic mice co-expressing ErbB2 and Cre recombinase in the mammary epithelium (Ursini- Siegel et al, 2008). Although mammary epithelial disruption of ILK had little impact on normal mammary gland development (Supplementary Figure S1A), loss of ILK function in ErbB2-expressing epithelium resulted in a profound proliferative block that was correlated with a dramatic impact in ErbB2 tumor onset and penetrance.…”