title: Prognostic value of the hDMP1-ARF-Hdm2-p53 pathway in breast cancer.
abstract: Our recent study showed critical roles of Dmp1 as a sensor of oncogenic Ras, HER2/neu signaling and activation of the Arf-p53 pathway. To elucidate the role of human DMP1 (hDMP1) in breast cancer, one hundred and ten pairs of human breast cancer specimen were studied for the alterations of the hDMP1-ARF-Hdm2-p53 pathway with follow up of clinical outcomes. Loss of heterozygosity (LOH) of the hDMP1 locus was found in 42% of human breast carcinomas, while that of INK4a/ARF and p53 were found in 20 and 34%, respectively. Hdm2 amplification was found in 13% of the same sample, which was found independently of LOH for hDMP1. Conversely, LOH for hDMP1 was found in mutually exclusive fashion with that of INK4a/ARF and p53, and was associated with low Ki67 index and diploid karyotype. Consistently, LOH for hDMP1 was associated with luminal A category and longer relapse-free survival, while that of p53 was associated with non-luminal A and shorter survival. Thus, loss of hDMP1 could define a new disease category associated with prognosis of breast cancer patients. Human breast epithelial cells/cancer cells with wild-type p53 were sensitive to growth inhibition by activated Dmp1:ER while those that delete p14(ARF) or p53, and/or Hdm2 amplification showed partial or nearly complete resistance, indicating that p53 is a critical target for hDMP1 to exhibit its biological activity.
authors.affiliation: Department of Pathology, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC 27157 USA.
authors.forename: D
authors.initials: D
authors.lastname: Maglic
authors.forename: S
authors.initials: S
authors.lastname: Zhu
authors.forename: E A
authors.initials: EA
authors.lastname: Fry
authors.forename: P
authors.initials: P
authors.lastname: Taneja
authors.forename: F
authors.initials: F
authors.lastname: Kai
authors.forename: R D
authors.initials: RD
authors.lastname: Kendig
authors.forename: T
authors.initials: T
authors.lastname: Sugiyama
authors.forename: L D
authors.initials: LD
authors.lastname: Miller
authors.forename: M C
authors.initials: MC
authors.lastname: Willingham
authors.forename: K
authors.initials: K
authors.lastname: Inoue
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000401:mortality* / Q000473:pathology; D045744:Cell Line, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000502:physiology; D005260:Female; D006801:Humans; D019656:Loss of Heterozygosity; D009361:Neoplasm Invasiveness; D011379:Prognosis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000502:physiology*; D015398:Signal Transduction; D014157:Transcription Factors / Q000502:physiology*; D025803:Tumor Suppressor Protein p14ARF / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; C491126:DMTF1 protein, human; C495901:TP53 protein, human; D014157:Transcription Factors; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2