To study phenotype-genotype correlations, ErbB/Ras pathway
tumors (transgenic for ErbB2, c-Neu, mutants of c-Neu, polyomavirus middle T antigene (PyV-mT), Ras, and bi-transgenic for ErbB2/Neu with ErbB3 and with
progesterone receptor) from four different institutions were histopathologically compared with Wnt pathway
tumors [transgenes Wnt1, Wnt10b, dominant-negative
glycogen synthase kinase 3-beta,
beta-Catenin, and spontaneous mutants of
adenomatous polyposis coli gene (Apc)]. ErbB/Ras pathway
tumors tend to form solid nodules consisting of poorly differentiated cells with abundant cytoplasm. ErbB/Ras pathway
tumors also have scanty stroma and lack myoepithelial or squamous differentiation. In contrast, Wnt pathway
tumors exhibit myoepithelial, acinar, or glandular differentiation, and, frequently, combinations of these. Squamous
metaplasia is frequent and may include transdifferentiation to epidermal and pilar structures. Most Wnt pathway
tumors form caricatures of elongated, branched ductules, and have well-developed stroma, inflammatory infiltrates, and pushing margins.
Tumors transgenic for interacting genes such as
protein kinase CK2alpha (
casein kinase IIalpha), and the
fibroblast growth factors (Fgf) Int2/Fgf3 or
keratinocyte growth factor (Kgf/Fgf7) also have the Wnt pathway phenotype. Because the
tumors from the ErbB/Ras and the Wnt pathway are so distinct and can be readily identified using routine
hematoxylin and
eosin sections, we suggest that pathway pathology is applicable in both basic and clinical
cancer research.