Email updates

Keep up to date with the latest news and content from BMC Cancer and BioMed Central.

Open Access Research article

p27Kip1 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 and Konstantin Christov1*

Author Affiliations

1 University of Illinois at Chicago, Department of Surgery, Division of Surgical Oncology, 840 S. Wood St, Chicago, IL 60612 USA

2 Laboratory of Molecular Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA

3 Department of Endocrinology, Medical University, ul. Zdrave No.2, Sofia, Bulgaria

4 Department of Molecular Pharmacology and Biological Chemistry, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, 303 E. Superior, Lurie 3-113 Chicago, IL 60611 USA

For all author emails, please log on.

BMC Cancer 2010, 10:541  doi:10.1186/1471-2407-10-541

Published: 8 October 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, 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.