Matthias J. Szabolcs, MD

Among my scientific contributions relevant to this project is the analysis of various genetically engineered mouse models (GEMs), which generate cancerous and precancerous lesions and correlate such lesions with those occurring in humans. One publication in Carcinogenesis 2006 (ref. 1), describes an aggressive subtype of prostate cancer generated by conditional overexpression of the Erbb2/Neu oncogene in mouse prostatic apical cells with a comprehensive gene expression analysis which revealed concomitant overexpression of Egfr, Erbb3 and phosphorylated androgen receptor in such cancers. This was confirmed by tissue microarray analysis of both human and mouse tissues demonstrating that in human prostate cancer heterodimerization of either EGFR or NEU with ERBB3 rather than the EGFR/NEU heterodimer promote tumorigenesis and tumor progression with respect to the Erbb pathway. My task was to perform the histopathological and immunohistochemical analysis of all tissues including scoring of all tissue microarrays for EGRF, NEU and ERBB3. A similar project was the study of the relation of the NOTCH1 receptor with downstream expression of c-MYC in mouse and human breast cancer (ref 2, 3), which was done on a molecular and protein level establishing MYC as a molecular target of NOTCH signaling. High protein levels of MYC in human tumors correlated significantly with increased Notch signaling using immunohistochemistry on tissue microarrays. I performed the immunohistochemical analysis of all tumors for this project. With respect to breast cancers in GEMs lacking the BRCA1/BARD1 heterodimer I could establish that their morphology resembles those of basal-like breast cancers in humans. Consequently such GEM models were used to dissect, which binding sites, binding partners and enzymatic functions of BRCA1 are important for its tumor suppression function (ref 4,5,6). A further study established IRS2 as potential pharmacological target for cancers with inactivation of the PTEN tumor suppressor demonstrating lack of progression to invasive carcinoma in GEMs deficient for this protein and high levels of IRS2 in human cancer with PTEN inactivation (ref 7) based on histological and immunohistochemical analysis. With respect to pharmacological targets and agents for cancer therapy, I conducted the analysis for several projects validating 1) IGF1R as a potential target for KRAS induced basal cell-like breast cancer in mice (ref 8), 2) a direct c-MYC inhibitor reducing pancreas cancer of mice (ref. 9), 3) the combination of metformin and elrotinib and metformin have a synergistic effect on human basal cell cancer (ref. 10) and 4) the role of Ctip in Brca1 deleted breast cancer models (ref 11).