title: Genetic deletion of microsomal prostaglandin E synthase-1 suppresses mouse mammary tumor growth and angiogenesis.
abstract: The cyclooxygenase/prostaglandin (COX/PG) signaling pathway is of central importance in inflammation and neoplasia. COX inhibitors are widely used for analgesia and also have demonstrated activity for cancer prophylaxis. However, cardiovascular toxicity associated with this drug class diminishes their clinical utility and motivates the development of safer approaches both for pain relief and cancer prevention. The terminal synthase microsomal PGE synthase-1 (mPGES-1) has attracted considerable attention as a potential target. Overexpression of mPGES-1 has been observed in both colorectal and breast cancers, and gene knockout and overexpression approaches have established a role for mPGES-1 in gastrointestinal carcinogenesis. Here we evaluate the contribution of mPGES-1 to mammary tumorigenesis using a gene knockout approach. Mice deficient in mPGES-1 were crossed with a strain in which breast cancer is driven by overexpression of human epidermal growth factor receptor 2 (HER2/neu). Loss of mPGES-1 was associated with a substantial reduction in intramammary PGE2 levels, aromatase activity, and angiogenesis in mammary glands from HER2/neu transgenic mice. Consistent with these findings, we observed a significant reduction in multiplicity of tumors ≥1mm in diameter, suggesting that mPGES-1 contributes to mammary tumor growth. Our data identify mPGES-1 as a potential anti-breast cancer target.
authors.affiliation: Department of Cell & Developmental Biology and Weill Cornell Cancer Center, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA. Electronic address: LRHOWE@MED.CORNELL.EDU.
authors.forename: Louise R
authors.initials: LR
authors.lastname: Howe
authors.forename: Kotha
authors.initials: K
authors.lastname: Subbaramaiah
authors.forename: Claire V
authors.initials: CV
authors.lastname: Kent
authors.forename: Xi K
authors.initials: XK
authors.lastname: Zhou
authors.forename: Sung-Hee
authors.initials: SH
authors.lastname: Chang
authors.forename: Timothy
authors.initials: T
authors.lastname: Hla
authors.forename: Per-Johan
authors.initials: PJ
authors.lastname: Jakobsson
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Hudis
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Dannenberg
mesh_terms: D000818:Animals; D001141:Aromatase / Q000378:metabolism; D063646:Carcinogenesis / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000172:deficiency* / Q000235:genetics*; D008321:Mammary Glands, Animal / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply* / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D055806:Microvessels / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000235:genetics*; D000071876:Prostaglandin-E Synthases; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D001141:Aromatase; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; D018719:Erb-b2 Receptor Tyrosine Kinases; D042461:Vascular Endothelial Growth Factor A; C000605862:PTGES protein, human; C000605865:Ptges protein, mouse
keywords: Angiogenesis; Aromatase; Breast cancer; Mouse; PGE(2); mPGES-1