Taylor et al. BMC Cancer 2010, 10:541 http://www.biomedcentral.com/1471-2407/10/541 R E S E A R C H A R T I C L E Open Access Kip1 p27 deficiency promotes prostate carcinogenesis but does not affect the efficacy of retinoids in suppressing the neoplastic process Winna Taylor1, Amanda Mathias1, Arshia Ali1, Hengning Ke2, Nikolay Stoynev3, Anne Shilkaitis1, Albert Green1, Hiroaki Kiyokawa4, Konstantin Christov1* 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, 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. Methods: p27Kip1 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. 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. Conclusions: This 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. Background Various risk factors, such as race (with black men having the highest risk), family history, and genetic predisposi- tion appear to play principal roles in the development and progression of prostate cancer [1-3]. Over the last several years, increasing attention has been paid to the role of p27Kip1 expression in the development and pro- gression of various tumors, including prostate cancer. Human tumors lacking p27Kip1 appear more malignant than those with high levels of the gene’s expression [4,5]. Normal prostate epithelial cells (PEC) exhibit abundant * Correspondence: christov@uic.edu 1University of Illinois at Chicago, Department of Surgery, Division of Surgical Oncology, 840 S. Wood St, Chicago, IL 60612 USA Full list of author information is available at the end of the article amounts of p27Kip1 protein and mRNA, whereas in benign prostate hyperplasia (BPH) p27Kip1 decreases to undetectable levels. In contrast to BPH, most prostate carcinomas contain p27 mRNA but low to undetectable levels of p27Kip1 protein, suggesting post-transcriptional alterations in the gene’s activity [6,7]. Little is known regarding when in the course of prostate carcinogenesis disassociation between p27 mRNA and protein expres- sion occurs or whether p27Kip1 alone or in cooperation with other genes is involved in mediating the response of prostate pre-malignant and tumor cells to various che- mopreventive and antitumor agents. p27kip1 is a cell cycle suppressor gene, whose protein product is a negative regulator of cyclin dependent kinases (CDKs) [8-10]. Cyclin dependent kinases-2/4/6 © 2010 Taylor et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.