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Open Access 01-12-2010 | Research article

p27^Kip1deficiency promotes prostate carcinogenesis but does not affect the efficacy of retinoids in suppressing the neoplastic process

Authors: Winna Taylor, Amanda Mathias, Arshia Ali, Hengning Ke, Nikolay Stoynev, Anne Shilkaitis, Albert Green, Hiroaki Kiyokawa, Konstantin Christov

Published in: BMC Cancer | Issue 1/2010

Abstract

Background

p27 is a cell cycle suppressor gene, whose protein is a negative regulator of cyclin/cdk complexes. p27 is also a potential target of retinoids in cancer prevention studies. In benign prostate hyperplasia (BPH), and in most carcinomas, p27^Kip1 is down-regulated, suggesting its potential resistance to retinoids. To test this hypothesis, we examined the efficacy of 9-cis retinoic acid (9cRA) to suppress prostate cell proliferation (PECP) and carcinogenesis in p27^Kip1 deficient mice.

Methods

p27^Kip1 deficient (-/-), heterozygous (+/-) and homozygous (+/+) mice were treated for 7 days with testosterone, 9cRA, or with both, and cell proliferation in dorsolateral prostate (DLP) was determined by BrdU labeling. Prostate carcinogenesis was induced by N-Methyl-N-Nitrosourea (MNU) and hormone stimulation.

Results

PECP in DLP of two-month-old mice of all genotypes was similar but significantly increased in old p27-/- mice only. Testosterone treatment increased PECP in all three p27 genotypes with the highest values in p27-/- mice. p27^Kip1 deficiency did not affect the response of PEC to 9cRA and to 9cRA+testosterone. The decrease of p27^Kip1 in p27+/- and p27-/- mice progressively increased the incidence and frequency of PIN and tumors. 9cRA suppressed PIN in all three p27 genotypes and this was associated with decreased PECP and increased cellular senescence.

Conclusions

This data indicates that p27^Kip1 deficiency promotes prostate cell proliferation and carcinogenesis but does not affect 9cRA's potential to suppress prostate carcinogenesis, suggesting that patients with PIN and carcinomas lacking or having a low level of p27^Kip1 expression may also benefit from clinical trials with retinoids.

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The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/10/541/prepub

Title: p27Kip1deficiency promotes prostate carcinogenesis but does not affect the efficacy of retinoids in suppressing the neoplastic process
Authors: Winna Taylor
Amanda Mathias
Arshia Ali
Hengning Ke
Nikolay Stoynev
Anne Shilkaitis
Albert Green
Hiroaki Kiyokawa
Konstantin Christov
Publication date: 01-12-2010
Publisher: BioMed Central
Published in: BMC Cancer / Issue 1/2010
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/1471-2407-10-541

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