Skip to main content

TP53, CDKN2A/P16, and NFE2L2/NRF2 regulate the incidence of pure- and combined-small cell lung cancer in mice.

Publication ,  Journal Article
Hamad, SH; Montgomery, SA; Simon, JM; Bowman, BM; Spainhower, KB; Murphy, RM; Knudsen, ES; Fenton, SE; Randell, SH; Holt, JR; Hayes, DN ...
Published in: Oncogene
June 2022

Studies have shown that Nrf2E79Q/+ is one of the most common mutations found in human tumors. To elucidate how this genetic change contributes to lung cancer, we compared lung tumor development in a genetically-engineered mouse model (GEMM) with dual Trp53/p16 loss, the most common mutations found in human lung tumors, in the presence or absence of Nrf2E79Q/+. Trp53/p16-deficient mice developed combined-small cell lung cancer (C-SCLC), a mixture of pure-SCLC (P-SCLC) and large cell neuroendocrine carcinoma. Mice possessing the LSL-Nrf2E79Q mutation showed no difference in the incidence or latency of C-SCLC compared with Nrf2+/+ mice. However, these tumors did not express NRF2 despite Cre-induced recombination of the LSL-Nrf2E79Q allele. Trp53/p16-deficient mice also developed P-SCLC, where activation of the NRF2E79Q mutation associated with a higher incidence of this tumor type. All C-SCLCs and P-SCLCs were positive for NE-markers, NKX1-2 (a lung cancer marker) and negative for P63 (a squamous cell marker), while only P-SCLC expressed NRF2 by immunohistochemistry. Analysis of a consensus NRF2 pathway signature in human NE+-lung tumors showed variable activation of NRF2 signaling. Our study characterizes the first GEMM that develops C-SCLC, a poorly-studied human cancer and implicates a role for NRF2 activation in SCLC development.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Oncogene

DOI

EISSN

1476-5594

Publication Date

June 2022

Volume

41

Issue

25

Start / End Page

3423 / 3432

Location

England

Related Subject Headings

  • Tumor Suppressor Protein p53
  • Transcription Factors
  • Small Cell Lung Carcinoma
  • Oncology & Carcinogenesis
  • Nuclear Proteins
  • NF-E2-Related Factor 2
  • Mice
  • Lung Neoplasms
  • Incidence
  • Humans
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Hamad, S. H., Montgomery, S. A., Simon, J. M., Bowman, B. M., Spainhower, K. B., Murphy, R. M., … Weissman, B. E. (2022). TP53, CDKN2A/P16, and NFE2L2/NRF2 regulate the incidence of pure- and combined-small cell lung cancer in mice. Oncogene, 41(25), 3423–3432. https://doi.org/10.1038/s41388-022-02348-0
Hamad, Samera H., Stephanie A. Montgomery, Jeremy M. Simon, Brittany M. Bowman, Kyle B. Spainhower, Ryan M. Murphy, Erik S. Knudsen, et al. “TP53, CDKN2A/P16, and NFE2L2/NRF2 regulate the incidence of pure- and combined-small cell lung cancer in mice.Oncogene 41, no. 25 (June 2022): 3423–32. https://doi.org/10.1038/s41388-022-02348-0.
Hamad SH, Montgomery SA, Simon JM, Bowman BM, Spainhower KB, Murphy RM, et al. TP53, CDKN2A/P16, and NFE2L2/NRF2 regulate the incidence of pure- and combined-small cell lung cancer in mice. Oncogene. 2022 Jun;41(25):3423–32.
Hamad, Samera H., et al. “TP53, CDKN2A/P16, and NFE2L2/NRF2 regulate the incidence of pure- and combined-small cell lung cancer in mice.Oncogene, vol. 41, no. 25, June 2022, pp. 3423–32. Pubmed, doi:10.1038/s41388-022-02348-0.
Hamad SH, Montgomery SA, Simon JM, Bowman BM, Spainhower KB, Murphy RM, Knudsen ES, Fenton SE, Randell SH, Holt JR, Hayes DN, Witkiewicz AK, Oliver TG, Major MB, Weissman BE. TP53, CDKN2A/P16, and NFE2L2/NRF2 regulate the incidence of pure- and combined-small cell lung cancer in mice. Oncogene. 2022 Jun;41(25):3423–3432.

Published In

Oncogene

DOI

EISSN

1476-5594

Publication Date

June 2022

Volume

41

Issue

25

Start / End Page

3423 / 3432

Location

England

Related Subject Headings

  • Tumor Suppressor Protein p53
  • Transcription Factors
  • Small Cell Lung Carcinoma
  • Oncology & Carcinogenesis
  • Nuclear Proteins
  • NF-E2-Related Factor 2
  • Mice
  • Lung Neoplasms
  • Incidence
  • Humans