Deletion of the p16INK4a tumor suppressor and expression of the androgen receptor induce sarcomatoid carcinomas with signet ring cells in the mouse prostate

Dong Hong Lee, Eun Jeong Yu, Joseph Aldahl, Julie Yang, Yongfeng He, Erika Hooker, Vien Le, Jiaqi Mi, Adam Olson, Huiqing Wu, Joseph Geradts, Guang Q. Xiao, Mark L. Gonzalgo, Robert D. Cardiff, Zijie Sun

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Abstract

The tumor suppressor p16Ink4a, encoded by the INK4a gene, is an inhibitor of cyclin D-dependent kinases 4 and 6, CDK4 and CDK6. This inhibition prevents the phosphorylation of the retinoblastoma protein (pRb), resulting in cellular senescence through inhibition of E2F-mediated transcription of S phase genes required for cell proliferation. The p16Ink4a plays an important role in tumor suppression, whereby its deletion, mutation, or epigenetic silencing is a frequently observed genetic alteration in prostate cancer. To assess its roles and related molecular mechanisms in prostate cancer initiation and progression, we generated a mouse model with conditional deletion of p16Ink4a in prostatic luminal epithelium. The mice underwent oncogenic transformation and developed prostatic intraepithelial neoplasia (PIN) from eight months of age, but failed to develop prostatic tumors. Given the prevalence of aberrant androgen signaling pathways in prostate cancer initiation and progression, we then generated R26hARL/wt:p16L/L: PB-Cre4 compound mice, in which conditional expression of the human AR transgene and deletion of p16Ink4a co-occur in prostatic luminal epithelial cells. While R26hARL/wt:PB-Cre4 mice showed no visible pathological changes, R26hARL/wt:p16L/L: PB-Cre4 compound mice displayed an early onset of high-grade PIN (HGPIN), prostatic carcinoma, and metastatic lesions. Strikingly, we observed tumors resembling human sarcomatoid carcinoma with intermixed focal regions of signet ring cell carcinoma (SRCC) in the prostates of the compound mice. Further characterization of these tumors showed they were of luminal epithelial cell origin, and featured characteristics of epithelial to mesenchymal transition (EMT) with enhanced proliferative and invasive capabilities. Our results not only implicate a biological role for AR expression and p16Ink4a deletion in the pathogenesis of prostatic SRCC, but also provide a new and unique genetically engineered mouse (GEM) model for investigating the molecular mechanisms for SRCC development.

Original languageEnglish (US)
Article numbere0211153
JournalPLoS One
Volume14
Issue number1
DOIs
StatePublished - Jan 1 2019

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Signet Ring Cell Carcinoma
Androgen Receptors
carcinoma
prostatic neoplasms
Tumors
Prostate
neoplasms
mice
Neoplasms
Prostatic Intraepithelial Neoplasia
Prostatic Neoplasms
cells
Genes
Cyclin D
epithelial cells
animal models
Retinoblastoma Protein
Phosphorylation
Cyclin-Dependent Kinase 6
Cell proliferation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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Deletion of the p16INK4a tumor suppressor and expression of the androgen receptor induce sarcomatoid carcinomas with signet ring cells in the mouse prostate. / Lee, Dong Hong; Yu, Eun Jeong; Aldahl, Joseph; Yang, Julie; He, Yongfeng; Hooker, Erika; Le, Vien; Mi, Jiaqi; Olson, Adam; Wu, Huiqing; Geradts, Joseph; Xiao, Guang Q.; Gonzalgo, Mark L.; Cardiff, Robert D.; Sun, Zijie.

In: PLoS One, Vol. 14, No. 1, e0211153, 01.01.2019.

Research output: Contribution to journalArticle

Lee, DH, Yu, EJ, Aldahl, J, Yang, J, He, Y, Hooker, E, Le, V, Mi, J, Olson, A, Wu, H, Geradts, J, Xiao, GQ, Gonzalgo, ML, Cardiff, RD & Sun, Z 2019, 'Deletion of the p16INK4a tumor suppressor and expression of the androgen receptor induce sarcomatoid carcinomas with signet ring cells in the mouse prostate', PLoS One, vol. 14, no. 1, e0211153. https://doi.org/10.1371/journal.pone.0211153
Lee, Dong Hong ; Yu, Eun Jeong ; Aldahl, Joseph ; Yang, Julie ; He, Yongfeng ; Hooker, Erika ; Le, Vien ; Mi, Jiaqi ; Olson, Adam ; Wu, Huiqing ; Geradts, Joseph ; Xiao, Guang Q. ; Gonzalgo, Mark L. ; Cardiff, Robert D. ; Sun, Zijie. / Deletion of the p16INK4a tumor suppressor and expression of the androgen receptor induce sarcomatoid carcinomas with signet ring cells in the mouse prostate. In: PLoS One. 2019 ; Vol. 14, No. 1.
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abstract = "The tumor suppressor p16Ink4a, encoded by the INK4a gene, is an inhibitor of cyclin D-dependent kinases 4 and 6, CDK4 and CDK6. This inhibition prevents the phosphorylation of the retinoblastoma protein (pRb), resulting in cellular senescence through inhibition of E2F-mediated transcription of S phase genes required for cell proliferation. The p16Ink4a plays an important role in tumor suppression, whereby its deletion, mutation, or epigenetic silencing is a frequently observed genetic alteration in prostate cancer. To assess its roles and related molecular mechanisms in prostate cancer initiation and progression, we generated a mouse model with conditional deletion of p16Ink4a in prostatic luminal epithelium. The mice underwent oncogenic transformation and developed prostatic intraepithelial neoplasia (PIN) from eight months of age, but failed to develop prostatic tumors. Given the prevalence of aberrant androgen signaling pathways in prostate cancer initiation and progression, we then generated R26hARL/wt:p16L/L: PB-Cre4 compound mice, in which conditional expression of the human AR transgene and deletion of p16Ink4a co-occur in prostatic luminal epithelial cells. While R26hARL/wt:PB-Cre4 mice showed no visible pathological changes, R26hARL/wt:p16L/L: PB-Cre4 compound mice displayed an early onset of high-grade PIN (HGPIN), prostatic carcinoma, and metastatic lesions. Strikingly, we observed tumors resembling human sarcomatoid carcinoma with intermixed focal regions of signet ring cell carcinoma (SRCC) in the prostates of the compound mice. Further characterization of these tumors showed they were of luminal epithelial cell origin, and featured characteristics of epithelial to mesenchymal transition (EMT) with enhanced proliferative and invasive capabilities. Our results not only implicate a biological role for AR expression and p16Ink4a deletion in the pathogenesis of prostatic SRCC, but also provide a new and unique genetically engineered mouse (GEM) model for investigating the molecular mechanisms for SRCC development.",
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AU - Lee, Dong Hong

AU - Yu, Eun Jeong

AU - Aldahl, Joseph

AU - Yang, Julie

AU - He, Yongfeng

AU - Hooker, Erika

AU - Le, Vien

AU - Mi, Jiaqi

AU - Olson, Adam

AU - Wu, Huiqing

AU - Geradts, Joseph

AU - Xiao, Guang Q.

AU - Gonzalgo, Mark L.

AU - Cardiff, Robert D.

AU - Sun, Zijie

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