Pathway pathology: the wnt and erbB mammary tumors

Human mammary cancer is frequently associated with the erbB pathway, whereas 'spontaneous' mouse mammary tumor virus (MMTV)-induced mammary tumors are associated with the wnt-1 pathway. Many members of both pathways have been studied in genetically engineered mice. Using examples from the UCD Mutant Mouse Pathology Laboratory, we studied the characteristics of both pathways and found that they have unique, identifiable phenotypes. These observations are the foundation for pathway pathology. Members of the wnt1 pathway tend to form variations of the classical, MMTV-induced, type A, B and P tumors described by Dunn. Wnt1 tumors are expansile, surrounded by dense stroma, develop around central ducts, retain myoepithelial differentiation, and frequently have squamous metaplasia. Examples include the following: wnt1, wnt10b, APC1, GSK, CKII, B-Catenin, and FGF mice. In contrast, members of the erbB pathway are more likely to resemble human tumors, to be invasive, lose myoepithelial differentiation, form solid nodular asymetrical masses budding from individual ducts, have less stroma, and be less metaplastic. Examples include the following: erbB2, PyV-mT, mutants and bigenics of erbB and PyV-mT, src, and ras. Interestingly, GEM tumors initiated by nuclear factors do not tend to have the characteristics of either of these pathways. Examples: myc and lef1. These observations suggest that the principles of pathway pathology can be applied to human tumors of the breast and other organs. This work was supported by the DAAD (AR, individual grant), the State of California, BCRP JB-0014, and RO1CA89140 from NCI.