Increased phospho-AKT is associated with loss of the androgen receptor during the progression of N-methyl-N-nitrosourea-induced prostate carcinogenesis in rats

• Published in: The Prostate Vol. 64; no. 2; pp. 186 - 199
• Main Authors: Liao, Zhiming, Wang, Shihua, Boileau, Thomas W.-M., Erdman Jr, John W., Clinton, Steven K.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.07.2005; Wiley-Liss
• Subjects: Alkylating Agents; androgen receptor; Animals; Biological and medical sciences; Disease Models, Animal; Disease Progression; Gynecology. Andrology. Obstetrics; Male; Male genital diseases; Medical sciences; Methylnitrosourea; Nephrology. Urinary tract diseases; nuclear morphometry; p-AKT; Phosphorylation; prostate cancer; Prostatic Neoplasms - chemically induced; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - physiopathology; Protein-Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; Rats; Receptors, Androgen - metabolism; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland; Andrology; Nephrology; Prognosis; Protein kinase B; Prostate disease; Rat; Nitrosoureas; Carcinogenesis; Evolution; rats; Male genital diseases; Urogenital system; Urinary system disease; Gynecology; Rodentia; Loss; Malignant tumor; Vertebrata; p-AKT; Mammalia; Animal; Androgen receptor; nuclear morphometry; Morphometry; Prostate cancer; Hormonal receptor
• ISSN: 0270-4137; 1097-0045
• DOI: 10.1002/pros.20224

BACKGROUND Characterization of molecular events during N‐methyl‐N‐nitrosourea (MNU)‐induced rat prostate carcinogenesis enhances the utility of this model for the preclinical assessment of preventive strategies. Androgen independence is typical of advanced human prostate cancer and may occur through multiple mechanisms including the loss of androgen receptor (AR) expression and the activation of alternative signaling pathways. METHODS We examined the interrelationships between AR and p‐AKT expression by immunohistochemical staining during MNU‐androgen‐induced prostate carcinogenesis in male Wistar‐Unilever rats. Histone nuclear staining and image analysis was employed to assess parallel changes in chromatin and nuclear structure. RESULTS The percentage of AR positive nuclei decreased (P < 0.01) as carcinogenesis progressed: hyperplasia (92%), atypical hyperplasia (92%), well‐differentiated adenocarcinoma (57%), moderately‐differentiated adenocarcinoma (19%), and poorly‐differentiated adenocarcinoma (10%). Conversely, p‐AKT staining increased significantly during carcinogenesis. Sparse staining was observed in normal tissues (0.2% of epithelial area) and hyperplastic lesions (0.1%), while expression increased significantly (P < 0.001) in atypical hyperplasia (7.6%), well‐differentiated adenocarcinoma (16.7%), moderately‐differentiated adenocarcinoma (19.6%), and poorly‐differentiated adenocarcinoma (17.4%). In parallel, nuclear morphometry revealed increased nuclear size, greater irregularity, and lower DNA compactness as cancers became more poorly differentiated. CONCLUSIONS In the MNU model, the progressive evolution of dominant tumor cell populations showing an increase in p‐AKT in parallel with a decline in AR staining suggests that activation of AKT signaling may be one of several mechanisms contributing to androgen insensitivity during prostate cancer progression. Our observations mimic findings suggested by human studies and support the relevance of the MNU model in preclinical studies of preventive strategies. © 2005 Wiley‐Liss, Inc.