p27Kip1deficiency promotes prostate carcinogenesis but does not affect the efficacy of retinoids in suppressing the neoplastic process

BMC Cancer

Research Article

Nikolay Stoynev¹  Hiroaki Kiyokawa²  Hengning Ke³  Amanda Mathias⁴  Arshia Ali⁴  Winna Taylor⁴  Albert Green⁴  Anne Shilkaitis⁴  Konstantin Christov⁴ 

[1] Department of Endocrinology, Medical University, ul. Zdrave No.2, Sofia, Bulgaria;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, 60611, Chicago, IL, USA;Laboratory of Molecular Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, 27709, NC, USA;University of Illinois at Chicago, Department of Surgery, Division of Surgical Oncology, 840 S. Wood St, 60612, Chicago, IL, USA;

关键词: Testosterone;    Benign Prostate Hyperplasia;    Retinoid;    Prostate Intraepithelial Neoplasia;    Prostate Epithelial Cell;   

DOI  :  10.1186/1471-2407-10-541

 received in 2010-04-28, accepted in 2010-10-08,  发布年份 2010

来源: Springer

【 摘 要 】

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.

【 授权许可】

Unknown   
© Taylor et al; licensee BioMed Central Ltd. 2010. This article is published under license to 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.