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Cooperation between Dmp1 loss and cyclin D1 overexpression in breast cancer

Sinan Zhu1, Ryan T Mott2, Elizabeth A Fry2

  • 1Department 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.

The American Journal of Pathology
|August 14, 2013
PubMed

Insights

Cyclin D1 overexpression and Dmp1 loss cooperate in breast cancer development. This interaction impacts cell-cycle regulators, promoting tumor growth and metastasis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Cycle Regulation

Background:

  • Cyclin D1 is a cell-cycle regulator often overexpressed in breast cancer.
  • Dmp1 is a tumor suppressor that counteracts oncogenic signals like Ras and HER2.
  • The interaction between Dmp1 and cyclin D1 in breast cancer is not well understood.

Purpose of the Study:

  • To investigate the biological significance of the Dmp1-cyclin D1 interplay in breast cancer.
  • To determine how cyclin D1 and Dmp1 influence cell-cycle arrest and apoptosis pathways.

Main Methods:

  • Assessed the interaction between cyclin D1 and Dmp1.
  • Analyzed the activation of Arf and Ink4a promoters by the Dmp1-cyclin D1 complex.
  • Utilized Dmp1-deficient and Dmp1-depleted cell models.
  • Examined Arf/Ink4a expression in pre-malignant mammary glands of genetically modified mice.
  • Investigated Dmp1 deletion and heterozygous status in mouse mammary carcinomas.

Main Results:

  • Cyclin D1 binds Dmp1 to activate Arf and Ink4a promoters, inducing apoptosis or cell-cycle delay in normal cells.
  • This induction is Dmp1-dependent, as it's absent in Dmp1-deficient or depleted cells.
  • Arf/Ink4a expression is increased in Dmp1(+/+);MMTV-cyclin D1 mice but down-regulated in Dmp1-deficient mice.
  • Dmp1 deletion occurs in 21% of MMTV-D1 and D1T286A mammary carcinomas.
  • Dmp1 heterozygous status accelerates tumorigenesis, reducing apoptosis and increasing metastasis.

Conclusions:

  • The Dmp1-cyclin D1 interaction plays a protective role in normal cells by inducing cell-cycle arrest.
  • Combined Dmp1 loss and cyclin D1 overexpression are critical drivers of breast cancer progression.
  • Dmp1 loss accelerates mammary tumorigenesis and promotes metastasis in the context of cyclin D1 overexpression.

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