Analysis of mammary carcinoma onset and progression in HER-2/neu oncogene transgenic mice reveals a lobular origin

Morphologic examinations of mammary neoplasias arising in BALB/c (H-2(d)) m ice carrying the activated rat HER-2/neu oncogene (BALB-NeuT), and in FVB ( H-2(q)) mice bearing the wild-type proto-oncogene (FVB-NeuN), indicate that both conditions result in a very human-like lobular carcinoma of alveolar type, whose histotype is the result of the preferential expression of HER-2 /neu products in the epithelium of lobular ducts and lobules. Detailed anal ysis of tumor progression indicates that transition from lobular hyperplasi a to overt carcinoma is associated with a high epithelial proliferation rat e, as assessed by anti-proliferating cell nuclear antigen immunostaining, a nd coincides with the activation and maximal extension of tumor angiogenic process as assessed by microvessel count (anti-CD31), anti-beta(3) integrin , and anti-laminin immunostaining. Neovascularization is accompanied by vas cular endothelial cell growth factor and basic fibroblast growth factor pro duction by hyperplastic epithelial cells. By contrast with the BALB-NeuT tu mors, E-cadherin expression is almost nonexistent in those arising in FVB-N euN mice and this may explain their high metastatic potential. Despite thei r different kinetics, however, the lung metastases observed in both strains are histologically similar and resemble the primary tumor. Both strains ca n thus be proposed as models for "in vivo" investigation of the origin and progression of the alveolar type of lobular mammary carcinoma and the testi ng of new therapeutic approaches.