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Novel frameshift mutation in the p16/INK4A tumor suppressor gene in canine breast cancer alters expression from the p16/INK4A/p14ARF locus§

Authors

  • Farruk M. Lutful Kabir,

    1. Department of Pathobiology, AURIC—Auburn University Research Initiative in Cancer, College of Veterinary Medicine Auburn University, Auburn, Alabama 36849
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  • Payal Agarwal,

    1. Department of Pathobiology, AURIC—Auburn University Research Initiative in Cancer, College of Veterinary Medicine Auburn University, Auburn, Alabama 36849
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  • Patricia DeInnocentes,

    1. Department of Pathobiology, AURIC—Auburn University Research Initiative in Cancer, College of Veterinary Medicine Auburn University, Auburn, Alabama 36849
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  • Jishan Zaman,

    1. Department of Pathobiology, AURIC—Auburn University Research Initiative in Cancer, College of Veterinary Medicine Auburn University, Auburn, Alabama 36849
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  • Allison Church Bird,

    1. Department of Pathobiology, AURIC—Auburn University Research Initiative in Cancer, College of Veterinary Medicine Auburn University, Auburn, Alabama 36849
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  • R. Curtis Bird

    Corresponding author
    1. Department of Pathobiology, AURIC—Auburn University Research Initiative in Cancer, College of Veterinary Medicine Auburn University, Auburn, Alabama 36849
    • Department of Pathobiology, Auburn University, 164 Greene Hall, College of Veterinary Medicine, Auburn, AL 36849-5519.
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  • Financial support: Animal Health and Disease Research Fund.

  • Conflict of interest: The authors state that there are no conflicts of interest.

  • §

    Farruk M. LutfulKabir and Payal Agarwal contributed equally to the manuscript.

Abstract

The INK4 family of cyclin-dependent kinase inhibitors (CKI) encode important cell cycle regulators that tightly control cell cycle during G1 to S phase. These related genes are considered tumor suppressors as loss of function contributes to the malignant phenotype. Expression of CKIs p16, p14ARF, or p15 were defective in six different canine mammary tumor (CMT) cell lines compared to normal thoracic canine fibroblasts. This suggests CKI defects are frequently responsible for neoplastic transformation in canine mammary carcinomas. p16 and p14ARF are two alternatively spliced products derived from the canine p16/INK4A/p14ARF gene locus. Despite omissions in the published p16 transcript and canine genome and the presence of GC-rich repeats, we determined the complete coding sequence of canine p16 revealing a deletion and frameshift mutation in p16 exon 1α in CMT28 cells. In addition, we determined canine p14ARF mRNA and protein sequences. Mapping of these mutations uncovered important aspects of p16 and p14ARF expression and defects in CMT28 cells shifting the p16 reading frame into p14ARF making a fusion protein that was predicted to be truncated, unstable and devoid of structural and functional integrity. This data describes an important neoplastic mechanism in the p16/INK4A/p14ARF locus in a spontaneous canine model of breast cancer. J. Cell. Biochem. 114: 56–66, 2012. © 2012 Wiley Periodicals, Inc.

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