title: Dmp1α inhibits HER2/neu-induced mammary tumorigenesis.
abstract: Our recent study shows a pivotal role of Dmp1 in quenching hyperproliferative signals from HER2 to the Arf-p53 pathway as a safety mechanism to prevent breast carcinogenesis. To directly demonstrate the role of Dmp1 in preventing HER2/neu-driven oncogenic transformation, we established Flag-Dmp1α transgenic mice (MDTG) under the control of the mouse mammary tumor virus (MMTV) promoter. The mice were viable but exhibited poorly developed mammary glands with markedly reduced milk production; thus more than half of parous females were unable to support the lives of new born pups. The mammary glands of the MDTG mice had very low Ki-67 expression but high levels of Arf, Ink4a, p53, and p21(Cip1), markers of senescence and accelerated aging. In all strains of generated MDTG;neu mice, tumor development was significantly delayed with decreased tumor weight. Tumors from MDTG;neu mice expressed Flag-Dmp1α and Ki-67 in a mutually exclusive fashion indicating that transgenic Dmp1α prevented tumor growth in vivo. Genomic DNA analyses showed that the Dmp1α transgene was partially lost in half of the MDTG;neu tumors, and Western blot analyses showed Dmp1α protein downregulation in 80% of the cases. Our data demonstrate critical roles of Dmp1 in preventing mammary tumorigenesis and raise the possibility of treating breast cancer by restoring Dmp1α expression.
authors.affiliation: Department of Pathology, Wake Forest University Health Sciences, Winston-Salem, North Carolina, United States of America ; Department of Cancer Biology, Wake Forest University Health Sciences, Winston-Salem, North Carolina, United States of America.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Fry
authors.forename: Pankaj
authors.initials: P
authors.lastname: Taneja
authors.forename: Dejan
authors.initials: D
authors.lastname: Maglic
authors.forename: Sinan
authors.initials: S
authors.lastname: Zhu
authors.forename: Guangchao
authors.initials: G
authors.lastname: Sui
authors.forename: Kazushi
authors.initials: K
authors.lastname: Inoue
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology*; D016326:Extracellular Matrix Proteins / Q000502:physiology*; D005260:Female; D018628:Gene Dosage; D006801:Humans; D007124:Immunoenzyme Techniques; D008325:Mammary Neoplasms, Experimental / Q000209:etiology / Q000401:mortality / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; D016326:Extracellular Matrix Proteins; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; C513308:Dmp1 protein, mouse; C524056:Erbb2 protein, mouse