title: Cystic duct dilatations and proliferative epithelial lesions in mouse mammary glands upon keratin 5 promoter-driven overexpression of cyclooxygenase-2.
abstract: Expression and pharmacological studies support a contribution of cyclooxygenase (COX)-2 to mammary gland tumorigenesis. In a recent transgenic study, mouse mammary tumor virus promoter-driven COX-2 expression in mouse mammary glands was shown to result in alveolar hyperplasia, dysplasia, and carcinomas after multiple rounds of pregnancy and lactation. In the study presented here, the effects of constitutive COX-2 overexpression in keratin 5-positive myoepithelial and luminal cells, driven by the keratin 5 promoter in a hormone-independent manner, was investigated. In nulliparous female mice, aberrant COX-2 overexpression correlated with increased prostaglandin (PG) E(2) levels and caused cystic duct dilatations, adenosis, and fibrosis whereas carcinomas developed rarely. This phenotype depended on COX-2-mediated PGE(2) synthesis and correlated with increased expression of proliferation-associated Ki67 in epithelial cells. No changes in the expression of apoptosis-related Bcl-2, caspase 3, or p53 were observed. Hyperproliferation of the mammary gland epithelial cells was associated with increased aromatase mRNA levels in this tissue. The spontaneous pathologies bear analogies to the human breast with fibrocystic changes. Intriguingly, strong COX-2 expression was observed in fibrocystic changes, as compared to low expression in normal breast epithelium. These results show for the first time that aberrant COX-2 expression contributes to the development of fibrocystic changes (FC), indicating that COX-2 and COX-2-mediated PG synthesis represent potential targets for the therapy of this most frequent benign disorder of the human breast.
authors.affiliation: Deutsches Krebsforschungszentrum, INF 280, 69120 Heidelberg, Germany. k.mueller-decker@dkfz-heidelberg.de
authors.forename: Karin
authors.initials: K
authors.lastname: Müller-Decker
authors.forename: Irina
authors.initials: I
authors.lastname: Berger
authors.forename: Karin
authors.initials: K
authors.lastname: Ackermann
authors.forename: Volker
authors.initials: V
authors.lastname: Ehemann
authors.forename: Svetlana
authors.initials: S
authors.lastname: Zoubova
authors.forename: Sebastian
authors.initials: S
authors.lastname: Aulmann
authors.forename: Walter
authors.initials: W
authors.lastname: Pyerin
authors.forename: Gerhard
authors.initials: G
authors.lastname: Fürstenberger
mesh_terms: D000818:Animals; D001706:Biopsy; D001940:Breast / Q000473:pathology; D053148:Caspase 3; D020169:Caspases / Q000096:biosynthesis; D049109:Cell Proliferation; D051546:Cyclooxygenase 2; D003549:Cystic Duct / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay; D004848:Epithelium / Q000473:pathology; D005260:Female; D005355:Fibrosis; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D053569:Keratin-15; D053555:Keratin-5; D007633:Keratins / Q000235:genetics*; D019394:Ki-67 Antigen / Q000096:biosynthesis; D008321:Mammary Glands, Animal / Q000378:metabolism*; D008565:Membrane Proteins; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D011401:Promoter Regions, Genetic; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019076:Transgenes; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis
chemical_list: C503940:KRT5 protein, human; D053569:Keratin-15; D053555:Keratin-5; D019394:Ki-67 Antigen; C492053:Krt15 protein, mouse; D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D007633:Keratins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases