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Attenuation of the retinoblastoma pathway in pancreatic neuroendocrine tumors due to increased cdk4/cdk6.

Publication ,  Journal Article
Tang, LH; Contractor, T; Clausen, R; Klimstra, DS; Du, Y-CN; Allen, PJ; Brennan, MF; Levine, AJ; Harris, CR
Published in: Clin Cancer Res
September 1, 2012

PURPOSE: In mice, genetic changes that inactivate the retinoblastoma tumor suppressor pathway often result in pancreatic neuroendocrine tumors (Pan-NETs). Conversely, in humans with this disease, mutations in genes of the retinoblastoma pathway have rarely been detected, even in genome-wide sequencing studies. In this study, we took a closer look at the role of the retinoblastoma pathway in human Pan-NETs. EXPERIMENTAL DESIGN: Pan-NET tumors from 92 patients were subjected to immunohistochemical staining for markers of the retinoblastoma pathway. To search for amplifications of retinoblastoma pathway genes, genomic DNAs from 26 tumors were subjected to copy number analysis. Finally, a small-molecule activator of the retinoblastoma pathway was tested for effects on the growth of two Pan-NET cell lines. RESULTS: A majority of tumors expressed high amounts of Cdk4 or its partner protein cyclin D1. High amounts of phosphorylated Rb1 were present in tumors that expressed high levels of Cdk4 or cyclin D1. The copy numbers of Cdk4 or the analogous kinase gene Cdk6 were increased in 19% of the tumors. Growth of the human Pan-NET cell line QGP1 was inhibited in a xenograft mouse model by the Cdk4/6 inhibitor, PD 0332991, which reactivates the retinoblastoma pathway. CONCLUSIONS: Inactivation of the retinoblastoma pathway was indicated for most Pan-NETs. Gene amplification and overexpression of Cdk4 and Cdk6 suggests that patients with Pan-NETs may respond strongly to Cdk4/6 inhibitors that are entering clinical trials.

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Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

September 1, 2012

Volume

18

Issue

17

Start / End Page

4612 / 4620

Location

United States

Related Subject Headings

  • Transplantation, Heterologous
  • Retinoblastoma Protein
  • Pyridines
  • Piperazines
  • Pancreatic Neoplasms
  • Oncology & Carcinogenesis
  • Neuroendocrine Tumors
  • Neoplasm Staging
  • Mutation
  • Middle Aged
 

Citation

APA
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MLA
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Tang, L. H., Contractor, T., Clausen, R., Klimstra, D. S., Du, Y.-C., Allen, P. J., … Harris, C. R. (2012). Attenuation of the retinoblastoma pathway in pancreatic neuroendocrine tumors due to increased cdk4/cdk6. Clin Cancer Res, 18(17), 4612–4620. https://doi.org/10.1158/1078-0432.CCR-11-3264
Tang, Laura H., Tanupriya Contractor, Richard Clausen, David S. Klimstra, Yi-Chieh Nancy Du, Peter J. Allen, Murray F. Brennan, Arnold J. Levine, and Chris R. Harris. “Attenuation of the retinoblastoma pathway in pancreatic neuroendocrine tumors due to increased cdk4/cdk6.Clin Cancer Res 18, no. 17 (September 1, 2012): 4612–20. https://doi.org/10.1158/1078-0432.CCR-11-3264.
Tang LH, Contractor T, Clausen R, Klimstra DS, Du Y-CN, Allen PJ, et al. Attenuation of the retinoblastoma pathway in pancreatic neuroendocrine tumors due to increased cdk4/cdk6. Clin Cancer Res. 2012 Sep 1;18(17):4612–20.
Tang, Laura H., et al. “Attenuation of the retinoblastoma pathway in pancreatic neuroendocrine tumors due to increased cdk4/cdk6.Clin Cancer Res, vol. 18, no. 17, Sept. 2012, pp. 4612–20. Pubmed, doi:10.1158/1078-0432.CCR-11-3264.
Tang LH, Contractor T, Clausen R, Klimstra DS, Du Y-CN, Allen PJ, Brennan MF, Levine AJ, Harris CR. Attenuation of the retinoblastoma pathway in pancreatic neuroendocrine tumors due to increased cdk4/cdk6. Clin Cancer Res. 2012 Sep 1;18(17):4612–4620.

Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

September 1, 2012

Volume

18

Issue

17

Start / End Page

4612 / 4620

Location

United States

Related Subject Headings

  • Transplantation, Heterologous
  • Retinoblastoma Protein
  • Pyridines
  • Piperazines
  • Pancreatic Neoplasms
  • Oncology & Carcinogenesis
  • Neuroendocrine Tumors
  • Neoplasm Staging
  • Mutation
  • Middle Aged