Treatment continued for 14 days, at which point the tumors were harvested. Results from our xenograft study show that Cl amidine www.selleckchem.com/products/MDV3100.html treat ment caused a significant reduction in the size of the tumors. Moreover, the analysis of tumor morphology by H E and PAS staining shows that, while tumors from the sham injected group dis played an advanced, potentially invasive, tumor pheno type, tumors from the Cl amidine treated group were much more be nign in appearance. Furthermore, the basement mem brane of Cl amidine treated tumors remained largely intact and had considerably less membrane breaching and leukocyte infiltration compared to the control group. These findings suggest that PADI2 plays an important role in comedo DCIS progression and that the inhibition of PADI activity can suppress tumor pro gression in vivo.

C Discussion In this study, we show that PADI2 is specifically upregu lated during mammary tumor progression and that the PADI inhibitor, Cl amidine, is effective in inhibiting the growth of PADI2 overexpressing cell lines in both 2D and 3D cultures. In addition, we demonstrate here for the first time that Cl amidine is successful in suppre sing tumor growth in a xenograft mouse model of com edo DCIS. Lastly, we document that PADI2 expression is highly correlated with HER2 ERBB2 overexpressing and luminal subtype breast cancers. Given the previous correlations between PADI2 and the HER2 ERBB2 oncogene, the goal of this study was to carry out an initial test of the hypothesis that PADI2 plays a role in breast cancer progression.

To accomplish this, we utilized the well established MCF10AT model and found that PADI2 expression was highly upregulated in MCF10DCIS cells, a cell line that forms comedo DCIS lesions that spontaneously progress to in vasive tumors. Our finding that PADI2 expres sion is highest in comedo DCIS lesions was perhaps not too surprising, given the close association of PADIs with inflammatory events. We are currently investigating the potential links be tween inflammatory signaling in these MCF10DCIS lesions and PADI2 activity. Interestingly, PADI2 expression in the MCF10AT series coincided with HER2 ERBB2 upregulation which, again, was not entirely unexpected given previous reports correlating PADI2 expression with HER2 ERBB2.

While we did find that HER2 ERBB2 and PADI2 protein expression correlated well across the MCF10AT cell lines, PADI2 protein levels are particularly high in the MCF10DCIS line, relative to HER2 ERBB2. We can not currently explain this finding. however, it is possible that cell line specific factors are stabilizing the PADI2 transcript, thus allowing for increased protein expression. GSK-3 While our data show a potential relationship between PADI2 and HER2 ERBB2 in the MCF10AT model, we wanted to examine this correlation at higher resolution.