Abstract 928: Deletion of mammary epithelial mPGES1 suppresses tumor development in mice: a possible effect of substrate re-diversion

Microsomal prostaglandin E2 synthase (mPGES1) is the terminal enzyme in cyclooxygenase (COX)-2-mediated prostaglandin (PG) E2 biosynthesis. The pro-tumor contributions of COX-2 and PGE2 are established as is the clinical efficacy of pharmacological COX-2 inhibition. However, in addition to the desired suppression of tumor PGE2, collateral loss of vascular endothelial COX-2-derived PGI2, an endogenous anti-platelet mediator, imposes a cardiovascular hazard that limits clinical use of COX-2 inhibitors. mPGES1 is a promising alternative target to interrupt COX-2-driven events in tumors without elevating cardiovascular risk. We engineered mice transgenic for an activated HER2/neu oncogene to lack mPGES1 in mammary epithelial cells (MEC; mPGES1 KOMEC ). mPGES1 KOMEC mice and their wild type (WT) littermates were sacrificed at 22 weeks and mammary glands harvested. Glands were sectioned, every 10th slide was H&E stained and scanned to obtain whole slide images. For each mouse, multiplicity was calculated using the slide containing the greatest number of lesions. Adjacent sections were immunostained for Ki67, caspase 3, and Factor VIII, to assess proliferation, apoptosis, and angiogenesis. Tumor multiplicity was significantly higher in WT compared to mPGES1 KOMEC mice (4.17 ± 1.05 [n=6] vs 0.29 ± 0.19 [n=7], respectively; p=0.002). In addition, in a second cohort of mice followed until tumors were palpable, mPGES1 KOMEC mice trended toward a longer tumor free period. Concordant with these observations, shRNA knock down (KD) of mPGES1 in mammary tumor cells dramatically suppressed their growth as orthotopic tumors in syngeneic immune competent WT hosts - 5 out of 6 non-target shRNA control tumors grew successfully while, in all cases, mPGES1 KD cells failed to grow. By immunohistochemistry, no difference was observed in proliferation or apoptosis between WT and mPGES1 KOMEC spontaneous tumors. Interestingly, and in contrast to our previous study of neu-driven mammary tumors in mice lacking MEC COX-2 (COX-2 KOMEC), vascularization was not different between mPEGS-1 KOMEC and WT spontaneous tumors suggesting divergence in the anti-tumorigenic mechanisms in mPEGS-1 KOMEC and COX-2 KOMEC tumors. Multiple studies of mPGES-1 deletion report re-diversion of COX-2-derived substrate to other prostanoid synthetic pathways, in particular PGD2. By Q-PCR, other than reduced mPGES1 mRNA, terminal prostanoid enzymes were not altered in mPGES1 KOMEC tumors. Interestingly, while th