Cooperation between Dmp1 loss and cyclin D1 overexpression in breast cancer.
Cyclin D1 is a component of the core cell-cycle machinery and is frequently overexpressed in breast cancer. It physically interacts with the tumor suppressor Dmp1 that attenuates the oncogenic signals from Ras and HER2 by inducing Arf/p53-dependent cell-cycle arrest. Currently, the biological significance of Dmp1-cyclin D1 interplay in breast cancer has not been determined. Here, we show that cyclin D1 bound to Dmp1 to activate both Arf and Ink4a promoters and, consequently, induced apoptosis or G2/M cell-cycle delay in normal cells to protect them from neoplastic transformation. The cyclin D1-induced Ink4a/Arf gene expression was dependent on Dmp1 because the induction was not detected in Dmp1-deficient or DMP1-depleted cells. Arf/Ink4a expression was increased in pre-malignant mammary glands from Dmp1(+/+);MMTV-cyclin D1 and Dmp1(+/+);MMTV-D1T286A mice but significantly down-regulated in those from Dmp1-deficient mice. Selective Dmp1 deletion was found in 21% of the MMTV-D1 and D1T286A mammary carcinomas, and the Dmp1 heterozygous status significantly accelerated mouse mammary tumorigenesis with reduced apoptosis and increased metastasis. Overall, our study reveals a pivotal role of combined Dmp1 loss and cyclin D1 overexpression in breast cancer.
Department of Pathology, Wake Forest School of Medicine, Winston-Salem, North Carolina; Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina; Graduate Program in Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina.
Sinan
S
Zhu
Department of Pathology, Wake Forest School of Medicine, Winston-Salem, North Carolina.
Ryan T
RT
Mott
Department of Pathology, Wake Forest School of Medicine, Winston-Salem, North Carolina.
Elizabeth A
EA
Fry
Department of Pathology, Wake Forest School of Medicine, Winston-Salem, North Carolina; Department of Biotechnology, Radiation Biosciences, Institute of Nuclear Medicine and Allied Science, SK Majumdar Road, Delhi, India.
Pankaj
P
Taneja
Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina.
George
G
Kulik
Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina. Electronic address: gsui@wakehealth.edu.
Guangchao
G
Sui
Department of Pathology, Wake Forest School of Medicine, Winston-Salem, North Carolina; Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina; Graduate Program in Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina. Electronic address: kinoue2@triad.rr.com.
Kazushi
K
Inoue
D000818:Animals; D017209:Apoptosis; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology; D019938:Cyclin D1 / Q000378:metabolism*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D016195:G2 Phase; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology*; D008324:Mammary Tumor Virus, Mouse / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D008938:Mitosis; D009154:Mutation / Q000235:genetics; D009362:Neoplasm Metastasis; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000172:deficiency* / Q000378:metabolism
C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; C491126:DMTF1 protein, human; C102116:Dmtf1 protein, mouse; D014157:Transcription Factors; D019938:Cyclin D1