ErbB2 is required for muscle spindle and myoblast cell survival.

Signaling mediated by ErbB2 is thought to play a critical role in numerous developmental processes. However, due to the embryonic lethality associated with the germ line inactivation of erbB2, its role in adult tissues remains largely obscure. Given the expression of ErbB2 at the neuromuscular junction, we have created a muscle-specific knockout to assess its role there. This resulted in viable mice with a progressive defect in proprioception due to loss of muscle spindles. Interestingly, a partial reduction of ErbB2 levels also reduced the number of muscle spindles. Although histological analysis of the muscle revealed an otherwise normal architecture, induction of muscle injury revealed a defect in muscle regeneration. Consistent with these observations, primary myoblasts lacking ErbB2 exhibit extensive apoptosis upon differentiation into myofibers. Taken together, these results illustrate a dual role for ErbB2 in both muscle spindle maintenance and survival of myoblasts.

Gene expression profiling of neu-induced mammary tumors from transgenic mice reveals genetic and morphological similarities to ErbB2-expressing human breast cancers.

Numerous studies have shown that the overexpression and amplification of ErbB2/Neu are observed in 20-30% of patients afflicted with breast cancer. Furthermore, it has also been observed that the elevated expression of ErbB2/Neu also correlates with poor prognosis and clinical outcome. Given the prevalence of this disease, we sought to create mouse models that mimic the human condition. In this study, we compared two mouse models expressing activated neu under the control of the endogenous and mouse mammary tumor virus promoters. Although histologically similar, the latency and metastatic potential of these tumors are remarkably different. Gene expression profiling of tumor RNA from the two Neu mouse models revealed distinctive and nonoverlapping patterns of gene expression. Consistent with noninvasive nature of the mammary tumors induced by expression of neu under the endogenous promoter, these tumors expressed a number of markers characteristic of a highly differentiated state. In addition to these differences, these analyses revealed that in contrast to the mouse mammary tumor virus-based Neu model, the endogenous promoter tumors expressed elevated levels of two genes (Grb7 and Cab1) that are closely linked to ErbB2 and often coamplified in noninvasive ductal carcinoma in situ. Furthermore, this analysis has revealed several transcription factors that may be involved in ErbB2-mediated tumorigenesis. Taken together, these results illustrate the similarity of the endogenously regulated Neu tumor model to the human disease.