TY - JOUR
T1 - Deletion of the p16 INK4a tumor suppressor and expression of the androgen receptor induce sarcomatoid carcinomas with signet ring cells in the mouse prostate
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
N1 - Funding Information:
This work was supported by NIHR01CA070297 for ZJS, NIHR01CA151623 for ZJS, NIHR01CA166894 for ZJS, NIHR21CA190021 for ZJS, NIHR01DK104941 for ZJS, and NIHP30CA033572 for JG. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Publisher Copyright:
© 2019 Lee et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2019/1
Y1 - 2019/1
N2 - The tumor suppressor p16 Ink4a , 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 p16 Ink4a 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 p16 Ink4a 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 R26hAR L/wt :p16 L/L : PB-Cre4 compound mice, in which conditional expression of the human AR transgene and deletion of p16 Ink4a co-occur in prostatic luminal epithelial cells. While R26hAR L/wt :PB-Cre4 mice showed no visible pathological changes, R26hAR L/wt :p16 L/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 p16 Ink4a 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.
AB - The tumor suppressor p16 Ink4a , 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 p16 Ink4a 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 p16 Ink4a 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 R26hAR L/wt :p16 L/L : PB-Cre4 compound mice, in which conditional expression of the human AR transgene and deletion of p16 Ink4a co-occur in prostatic luminal epithelial cells. While R26hAR L/wt :PB-Cre4 mice showed no visible pathological changes, R26hAR L/wt :p16 L/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 p16 Ink4a 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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U2 - 10.1371/journal.pone.0211153
DO - 10.1371/journal.pone.0211153
M3 - Article
C2 - 30677079
AN - SCOPUS:85060436792
VL - 14
JO - PLoS One
JF - PLoS One
SN - 1932-6203
IS - 1
M1 - e0211153
ER -