The purpose of this study is to analyze the RUNX3 protein expression in basal cell carcinoma, a neoplasm that is specifically linked to the Sonic Hedghog (SHH) pathway, in an attempt to explore possible interactions between the Runx family and the SHH pathway. To do so, we constructed a tissue microarray (TMA) of 30 BCC and corresponding normal skin, and analyzed the protein expression of both β-catenin and RUNX3. While the former is a commercially available antibody, the latter is (to our knowledge) the only available monoclonal RUNX3 antibody, produced in our laboratory. Our results on the expression of β-catenin in the BCC TMA mirror the known expression reported before. This served to fully confirm that our TMA is a faithful platform for the study of disease biomarkers and molecular mechanisms of basal cell carcinomas, as well as putative interactions of the SHH with other pathways. Our study shows that RUNX3 protein is expressed in normal skin, showing mild to moderate, distinct nuclear positivity in approximately 75% of all the epidermal cells, including those in the hair shaft. The analysis of 30 BCC arrayed showed that there is uniform nuclear expression of the RUNX3 antibody in all 30 cases. The expression was present in 100% of the BCC neoplastic cell, irrespective of the histological subtype, and with a degree of intensity higher to that identified in the normal epidermal counterparts. This represents RUNX3 protein overexpression in BCC when compared with the normal epidermis. The Runx genes play a complex role in tumorogenesis, including leukemias (RUNX1). In human epithelial neoplasms, RUNX3 downregulation is significantly associated with gastric cancer, acting as a tumour suppressor gene and, in particular, as the target of the TGF-β tumour suppressor pathway, and, representing one of the few TGF-β downstream transcription factors. Our study shows genuine RUNX3 protein overexpression in BCC, suggesting that RUNX3 is in someway linked to the SHH-Wnt pathway. More importantly, we present the first example of a human epithelial neoplasm with universal upregulation of one of the Runx genes. This observation provides further evidence of the complex and lineage-specific role of the Runx gene family. The fact that RUNX3 appears to act as a bona fide oncogene in a disease uniformly linked to the SHH-Wnt pathway offers a good opportunity for the future study of SHH-Runx interactions.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]