| Description |
In human breast cancer, molecular gene expression analysis classifies tumors into multiple subtypes: Luminal A and B, Her2, Normal&ndashlike, and Basal. Clinically, human breast cancers are treated based on histological markers, including hormone and growth receptors and special features. Variations in these markers inform both patient survival and treatment options. While the cell of origin for human breast tumors remains unknown, the prevailing hypothesis states that the diversity in human cancer is generated by the epithelial cell type diversity in the mammary gland. Standard breast cancer tumor models selectively express oncogenes in the mouse mammary gland through mammary specific hormone responsive promoters. Unfortunately, these promoters limit transformation to the luminal cell lineage of the breast, bypassing the myoepithelial and stem cell lineages. Using transgenic mice, resulting tumors are not diverse, generating mainly adenocarcinomas with either Luminal or Basal subtypes. We suspected the limited representation of mouse models could be credited to the transgenic mouse tumor cell of origin and that the ability to target a wide range of cells would improve tumor diversity outcomes. In contrast to the established transgenic mouse method, we created a lentiviral infection and transplantation system, where primary mammary epithelial cells are collected from donor mice, infected in vitro with oncogenic lentivirus, and transplanted into a cleared fat pad of recipient mice. With our model, a non&ndashhormone responsive promoter drives polyoma middle T oncogene expression in all mammary epithelial cell lineages. Using this lentiviral infection and transplantation method, we produced several mouse models for rare breast cancer phenotypes including adenosquamous, tubular, spindloid, and lipid&ndashrich. In addition, tumors produced both Basal and Luminal subtypes by microarray analysis. The most striking rare tumor phenotype was the lipid&ndashrich. This tumor secretes fats and milk protein into vacuoles, giving it a distinct morphology. We studied this tumor in depth using histological stains, microarray, and transplants to compare its features with the developmental state of pregnancy in the mammary gland, especially to the alveolar cell type. Finally, we propose an oncogenic targeting system to determine if the alveolar cell is a cell of origin for lipid rich tumors. |
