P27Kip1deficiency promotes prostate carcinogenesis but does not affect the efficacy of retinoids in suppressing the neoplastic process

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

doi:10.1186/1471-2407-10-541

Abstract

Backgroundp27 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, p27Kip1 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 p27Kip1 deficient mice.Methodsp27Kip1 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.ResultsPECP 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. p27Kip1 deficiency did not affect the response of PEC to 9cRA and to 9cRA+testosterone. The decrease of p27Kip1 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.ConclusionsThis data indicates that p27Kip1 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 p27Kip1 expression may also benefit from clinical trials with retinoids.

Highlights

Various risk factors, such as race, family history, and genetic predisposition appear to play principal roles in the development and progression of prostate cancer [1,2,3]
We examined whether p27Kip1 deficiency may affect MNU-induced prostate carcinogenesis and the efficacy of 9-cis retinoic acid (9cRA) in suppressing the neoplastic process
We found that p27Kip1 deficiency promotes prostate cell proliferation and carcinogenesis but does not affect the efficacy of 9cRA in suppressing prostate intraepithelial neoplasia (PIN) and tumor development

Summary

Introduction

Various risk factors, such as race (with black men having the highest risk), family history, and genetic predisposition appear to play principal roles in the development and progression of prostate cancer [1,2,3]. Over the last several years, increasing attention has been paid to the role of p27Kip expression in the development and progression of various tumors, including prostate cancer. Besson et al [18] discovered an oncogenic activity of p27Kip that causes stem cell expansion and a multiple tumor phenotype. They generated a knock-in mouse in which four amino acid substitutions in the CDKN1b gene product prevented its interaction with cyclins and CDKs (p27CK*) and found tumors in multiple organs, including: lung, pituitary, retina, adrenals, ovary, spleen, and lymphomas. No data has been published on the effects of p27Kip deficiency on chemically-induced prostate carcinogenesis and on the sensitivity of PEC to retinoids

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