Oncogenes, Progression and Biomarkers

Institution: University of California, Davis
Investigator(s): Robert Cardiff, M.D., Ph.D. -
Award Cycle: 1999 (Cycle V) Grant #: 5JB-0014 Award: $141,871
Award Type: IDEAS II
Research Priorities
Detection, Prognosis and Treatment>Imaging, Biomarkers, and Molecular Pathology: improving detection and diagnosis

Final Report (2001)
The ultimate benefit of this study would be to provide a basis for improving the clinical usefulness of biomarkers by determining which genetic changes result in structural changes within the breast, thus improving the basis for cancer therapy decisions. The underlying hypothesis of the study is that the oncogenes that control the transition of a breast cell from a normal to a cancerous state also cause unique predictable patterns of proteins that can be used as biomarkers.

A panel of antibodies were developed and used to study the immunohistochemistry (IHC) of biological markers (biomarkers) in mammary glands of genetically engineered mice (GEM) during tumor progression. The first nine months of this research grant was devoted to the development of a system for validating immunohistochemistry technologies with appropriate quality controls for specificity and sensitivity of the methodology (http://ccm.ucdavis.edu/tgmouse/protocols/ ). Next, the battery of antibodies were applied to study mammary biology in normal, pre-cancerous and cancerous tissues (http://ccm.ucdavis.edu/tvmouse/vmIHCMG/vmIHC-INDEX.html ).

Two mouse models known as PyV mT and c erbB2 were used as the "gold standards". The IHC studies in these models established the alveolar origin of the tumors. This was the first systematic study of IHC based biomarkers in the evolution of mammary tumorigenesis in genetically engineered mice. Using these mode system for comparison, the panel was applied to other models of human cancer. Several interesting biomarkers have been identified and studied. For example, osteopontin has been identified as a potential biomarker for metastatic potential in several GEM mammary tumor models.

More significantly, these IHC panels have allowed us to recognize that genetic defects in different genes in the same signal transduction pathway result in tumors that resemble each other. This has led to the development of an entirely new area of pathology, Pathway Pathology, that integrates structural and functional information to interpret cancer. Specific examples of Pathway Pathology can be found in the Wnt and the erbB2 pathways. The Wnt pathway controls some aspects of organ development and is activated in "spontaneous" virus induced tumors. Tumors with a virus induced activated Wnt pathway are characterized as developing branching ductal shapes. The erbB2 pathway controls growth and differentiation in the mammary gland. ErbB2 tumors develop as round, lobular shapes rather than branches. Detailed histological and immunohistochemical analysis of tumors from transgenic mice bearing many of the oncogenes from the Wnt pathway reveals that they all tend to share the same abnormally developed ductal structure. In contrast, the mice with the erbB2 related transgenes all share the lobular differentiation. These studies have led a better understanding of how cancer genes effect the appearance and biology of cancer.