Increased phospho-AKT is associated with loss of the androgen receptor during the progression of N-methyl-N-nitrosourea-induced prostate carcinogenesis in rats.
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.
Liao
Zhiming
Z
Division of Hematology and Oncology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA.
Wang
Shihua
S
Boileau
Thomas W-M
TW
Erdman
John W
JW
Clinton
Steven K
SK
D000477:Alkylating Agents; D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D008297:Male; D008770:Methylnitrosourea; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D011944:Receptors, Androgen / Q000378:metabolism*
D000477:Alkylating Agents; D011518:Proto-Oncogene Proteins; D011944:Receptors, Androgen; D008770:Methylnitrosourea; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt