Immunohistochemical study of androgen receptors in metastatic prostate cancer. Comparison of receptor content and response to hormonal therapy

Abstract

A longstanding goal has been to determine whether androgen receptor (AR) levels could be used to predict the clinical response of metastatic prostate cancer to androgen withdrawal therapy. A major limitation of previous studies was the use of homogenized tissue, which yields an average AR content for all cells. By AR immunohistochemical study using an antibody specific for AR the authors assessed nuclear AR content specifically in the malignant epithelial cells of prostate needle biopsy specimens of 17 patients with Stage D prostate cancer. The authors found that prostate cancer contains AR-positive and AR-negative malignant cells before androgen withdrawal therapy, but the percentage of AR-positive cells did not predict the time to tumor progression after therapy. There was no significant correlation between the percentage of AR-positive malignant cells and the time to tumor progression. When patients were divided into two groups based on the median time to progression, the percentage of AR-positive nuclei was not significantly different in poor responders versus good responders. When patients were divided into two groups based on the median percentage of receptor-positive nuclei, Kaplan-Meier estimates of the progression-free interval revealed no significant difference between the group of patients with AR-poor tumors and patients with AR-rich tumors. Potential explanations for these results are discussed. The authors conclude that the percentage of AR-positive nuclei is not a sufficient criterion to predict tumor behavior.

Expression and somatic mutation on androgen receptor gene in prostate cancer

“…Cancer cells which have lost their androgen receptors may acquire a growth advantage through the accumulation of several genetic changes. 20 Although some studies reported that the percentage of AR positive tumor cells did not correlate with the tumor grade or stage, 10 whereas others observed a significant correlation between AR immunostaining and histological grade. 6 In some reports, AR protein can be detected immunohistochemically in the majority of prostate cancer specimens which may contain mutations in the AR gene, however, in most samples it is not possible to determine the proportion of tumor cells expressing mutated AR.…”

“…6,7 Several studies showed some prognostic significances of AR expression, 8,9 but others have failed to identify such a relationship. 10 In addition, some studies have demonstrated that a high variability in AR expression was presented within an individual tumor, in particular advanced prostate cancers. 11,12 Somatic mutations on the AR gene have been detected in human prostate cancer.…”

Endothelin-1 in human prostatic carcinoma treated with androgen withdrawal

“…These data are in agreement with previous reports of AR-positive PC that is unresponsive to hormonal therapy. 14,15,16 Consequently, the percentage of AR-positive nuclei is not an absolute criterion for predicting response to hormonal therapy. 14 Various mechanisms can be proposed to explain unresponsive AR-positive PC , including some AR gene alterations, 17 which are not evident at the immunohistochemical level, although they can modify the functional status of ARs in malignant epithelial cells.…”

Differential androgen receptor signals in different cells explain why androgen-deprivation therapy of prostate cancer fails

“…AR is expressed throughout prostate cancer progression and its expression persists in the majority of patients with hormone-refractory disease (Cunha et al, 1987;Sadi et al, 1991;van der Kwast et al, 1991;Chodak et al, 1992;Hobisch et al, 1996;Mohler et al, 1996;Buchanan et al, 2001), and many AR mutations identified from hormone-refractory prostate tumors are capable of transactivation. These observations suggest that the eventual failure of ADT cannot be attributed simply to the loss of AR function.…”