| First Author | Fry EA | Year | 2013 |
| Journal | PLoS One | Volume | 8 |
| Issue | 10 | Pages | e77870 |
| PubMed ID | 24205004 | Mgi Jnum | J:209244 |
| Mgi Id | MGI:5566747 | Doi | 10.1371/journal.pone.0077870 |
| Citation | Fry EA, et al. (2013) Dmp1alpha inhibits HER2/neu-induced mammary tumorigenesis. PLoS One 8(10):e77870 |
| abstractText | 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-Dmp1alpha 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-Dmp1alpha and Ki-67 in a mutually exclusive fashion indicating that transgenic Dmp1alpha prevented tumor growth in vivo. Genomic DNA analyses showed that the Dmp1alpha transgene was partially lost in half of the MDTG;neu tumors, and Western blot analyses showed Dmp1alpha 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 Dmp1alpha expression. |
