The Contribution of Ras to MYC and Wnt-induced Tumor Progression

Activation of the MYC or Wnt pathway is common in human breast cancer and correlates with aggressive tumor behavior and a poor prognosis. However, the molecular mechanisms that contribute to the progression of breast cancer to a more aggressive state are unknown. To study mechanisms of mammary tumor progression, we used a tetracycline-regulatable system to induce MYC and Wnt1 in the mammary epithelium, which results in the stochastic formation of mammary adenocarcinomas. Progression to oncogene-independence was assessed by the behavior of tumors following doxycycline withdrawal and oncogene downregulation. While the majority of Wnt1-induced mammary tumors remained stably dependent upon Wnt1 for tumor maintenance and growth, the majority of MYC-induced mammary tumors progressed to MYC oncogene-independence and continued to grow in the absence of MYC transgene expression. Our data suggest that, in contrast to what has been shown by other inducible mouse models of carcinogenesis, targeting a single oncogenic pathway may not be sufficient in all contexts to induce clinical regression in cancer patients. Given the differential oncogene-dependent behavior seen in MYC and Wnt1-induced tumors, we investigated the potential molecular mechanisms by which this might occur. We demonstrated that MYC-induced tumors are preferentially associated with activating point mutations in Kras2 whereas Wnt1-induced tumors are preferentially associated with Hras1 mutations. Although c-MYC and Wnt1 were able to synergize in mammary tumorigenesis with either Kras2 or Hras1 , the preferential synergy of c-MYC with Kras2 and of Wnt1 with Hras1 provides a potential basis for their differential oncogene-independent behavior following oncogene inactivation. In support of this, biochemical analysis revealed that Kras2 mutant MYC and Wnt1-induced tumors have significantly higher levels of Ras and MAP kinase pathway activation compared to Wnt1-induced tumors with Hras1 mutations. Thus, these data support a model in which the preferential synergy of c-MYC with Kras2 and of Wnt1 with Hras1 during mammary tumorigenesis influences tumor progression. As MYC-induced tumors are associated with Kras2 mutations, these tumors tend to activate the MAP kinase pathway and progress to oncogene-independence. In contrast, as Wnt1-induced tumors are associated with Hras1 mutations and do not activate the MAP kinase pathway, they tend to remain dependent upon Wnt1 for tumor maintenance and growth