The role of Ink4a/Arf in ErbB2 mammary gland tumorigenesis

Mark D'Amico, Kongming Wu, Dolores Di Vizio, Anne T. Reutens, Mark Stahl, Maofu Fu, Chris Albanese, Robert G. Russell, William J. Muller, Michael White, Abdissa Negassa, Han Woong Lee, Ronald A. DePinho, Richard G. Pestell

Research output: Contribution to journalArticle

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Abstract

Most human tumors display inactivation of the p53 and the p16IK4/ pRb pathway. The Ink4a/alternative reading frame (ARF) locus encodes the p16INK4a and p14ARF (murine p19ARF) proteins. p16INK4a is deleted in 40-60% of breast cancer cell lines, and p16INKa inactivation by DNA methylation occurs in ≤30% of human breast cancers. In mice genetically heterozygous for p16INK4a or Ink4a/Arf, predisposition to specific tumor types is enhanced. Ink4a/Arf+/- mice have increased Eμ-Myc-induced lymphomagenesis and epidermal growth factor receptor-induced gliomagenesis. ErbB2 (epidermal growth factor receptor-related protein B2) is frequently overexpressed in human breast cancer and is sufficient for mammary tumorigenesis in vivo. We determined the role of heterozygosity at the Ink4a/Arf locus in ErbB2-induced mammary tumorigenesis. Compared with mouse mammary tumor virus-ErbB2 Ink4a/Arf+/- mice, mouse mammary tumor virus-ErbB2 Ink4a/Arfwt mammary tumors showed increased p16INK4a, reduced Ki-67 expression, and reduced cyclin D1 protein but increased mammary tumor apoptosis with no significant change in the risk of developing mammary tumors. These studies demonstrate the contribution of Ink4a/Arf heterozygosity to tumor progression is tissue specific in vivo. In view of the important role of Ink4a/Arf in response to chemotherapy, these transgenic mice may provide a useful model for testing breast tumor therapies.

Original languageEnglish (US)
Pages (from-to)3395-3402
Number of pages8
JournalCancer Research
Volume63
Issue number12
StatePublished - Jun 15 2003

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Human Mammary Glands
Carcinogenesis
Breast Neoplasms
Mouse mammary tumor virus
Epidermal Growth Factor Receptor
Breast
Tumor Suppressor Protein p14ARF
Reading Frames
Neoplasms
Proteins
Cyclin D1
DNA Methylation
Transgenic Mice
Apoptosis
Drug Therapy
Cell Line

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

D'Amico, M., Wu, K., Di Vizio, D., Reutens, A. T., Stahl, M., Fu, M., ... Pestell, R. G. (2003). The role of Ink4a/Arf in ErbB2 mammary gland tumorigenesis. Cancer Research, 63(12), 3395-3402.

The role of Ink4a/Arf in ErbB2 mammary gland tumorigenesis. / D'Amico, Mark; Wu, Kongming; Di Vizio, Dolores; Reutens, Anne T.; Stahl, Mark; Fu, Maofu; Albanese, Chris; Russell, Robert G.; Muller, William J.; White, Michael; Negassa, Abdissa; Lee, Han Woong; DePinho, Ronald A.; Pestell, Richard G.

In: Cancer Research, Vol. 63, No. 12, 15.06.2003, p. 3395-3402.

Research output: Contribution to journalArticle

D'Amico, M, Wu, K, Di Vizio, D, Reutens, AT, Stahl, M, Fu, M, Albanese, C, Russell, RG, Muller, WJ, White, M, Negassa, A, Lee, HW, DePinho, RA & Pestell, RG 2003, 'The role of Ink4a/Arf in ErbB2 mammary gland tumorigenesis', Cancer Research, vol. 63, no. 12, pp. 3395-3402.
D'Amico M, Wu K, Di Vizio D, Reutens AT, Stahl M, Fu M et al. The role of Ink4a/Arf in ErbB2 mammary gland tumorigenesis. Cancer Research. 2003 Jun 15;63(12):3395-3402.
D'Amico, Mark ; Wu, Kongming ; Di Vizio, Dolores ; Reutens, Anne T. ; Stahl, Mark ; Fu, Maofu ; Albanese, Chris ; Russell, Robert G. ; Muller, William J. ; White, Michael ; Negassa, Abdissa ; Lee, Han Woong ; DePinho, Ronald A. ; Pestell, Richard G. / The role of Ink4a/Arf in ErbB2 mammary gland tumorigenesis. In: Cancer Research. 2003 ; Vol. 63, No. 12. pp. 3395-3402.
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abstract = "Most human tumors display inactivation of the p53 and the p16IK4/ pRb pathway. The Ink4a/alternative reading frame (ARF) locus encodes the p16INK4a and p14ARF (murine p19ARF) proteins. p16INK4a is deleted in 40-60{\%} of breast cancer cell lines, and p16INKa inactivation by DNA methylation occurs in ≤30{\%} of human breast cancers. In mice genetically heterozygous for p16INK4a or Ink4a/Arf, predisposition to specific tumor types is enhanced. Ink4a/Arf+/- mice have increased Eμ-Myc-induced lymphomagenesis and epidermal growth factor receptor-induced gliomagenesis. ErbB2 (epidermal growth factor receptor-related protein B2) is frequently overexpressed in human breast cancer and is sufficient for mammary tumorigenesis in vivo. We determined the role of heterozygosity at the Ink4a/Arf locus in ErbB2-induced mammary tumorigenesis. Compared with mouse mammary tumor virus-ErbB2 Ink4a/Arf+/- mice, mouse mammary tumor virus-ErbB2 Ink4a/Arfwt mammary tumors showed increased p16INK4a, reduced Ki-67 expression, and reduced cyclin D1 protein but increased mammary tumor apoptosis with no significant change in the risk of developing mammary tumors. These studies demonstrate the contribution of Ink4a/Arf heterozygosity to tumor progression is tissue specific in vivo. In view of the important role of Ink4a/Arf in response to chemotherapy, these transgenic mice may provide a useful model for testing breast tumor therapies.",
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