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Human androgen receptor expression in prostate cancer following androgen ablation
R de Vere White1, F Meyers, S G Chi
1Department of Urology, University of California Davis School of Medicine, Sacramento 95817, USA.
Objective:
Metastatic prostate cancer kills patients because their tumor cells fail to respond to combined androgen blockade (CAB) or respond and then relapse. To understand the molecular basis of androgen-insensitive growth of prostate tumor cells, we evaluated changes in human androgen receptor gene (hAR) mRNA levels in patients with prostate cancer treated with CAB.
Methods:
The study was carried out using quantitative reverse-transcriptase polymerase chain reaction analysis. The level of hAR mRNA were compared to serum prostate-specific antigen and the mutant status of p53 in the tumor.
Results:
hAR was expressed in 44 of 46 tumors from untreated patients, as opposed to 30 of 45 from those who had received CAB (p = 0.001). These 30 were from 8 of 9 stage D patients and from 22 of 36 patients on downsizing CAB therapy prior to radical prostatectomy. Expression was most often seen in high stages (56% of stage B vs. 89% of stage D) and high grades (52% of Gleason 3-7 vs. 92% of Gleason 8-10, p = 0.015). No tumor with a missense p53 mutation had hAR expression following CAB. Twenty-two patients following CAB were found to have undetectable serum prostate-specific antigen levels, while their tumor expressed hAR.
Conclusions:
hAR expression after CAB is seen preferentially in high-grade, high-stage tumors, the type of prostate carcinomas that fail to have a durable remission. Undetectable serum prostate-specific antigen from tumors that remain hAR positive may predict relapse after hormonal ablative therapy.
Insights
Prostate cancer tumors expressing human androgen receptor (hAR) after treatment may indicate resistance to therapy. High-grade, advanced tumors are more likely to show hAR expression, potentially predicting relapse.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Metastatic prostate cancer poses a significant threat due to treatment resistance and relapse.
- Understanding the molecular mechanisms of androgen-insensitive growth is crucial for improving patient outcomes.
Purpose of the Study:
- To investigate changes in human androgen receptor (hAR) gene mRNA levels in prostate cancer patients undergoing combined androgen blockade (CAB).
- To elucidate the molecular basis of androgen-insensitive growth in prostate tumor cells.
Main Methods:
- Quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) was used to analyze hAR mRNA levels.
- hAR mRNA levels were correlated with serum prostate-specific antigen (PSA) and p53 mutation status.
Main Results:
- hAR expression was detected in a significant proportion of tumors after CAB, particularly in high-stage and high-grade cancers.
- Tumors with missense p53 mutations did not exhibit hAR expression post-CAB.
- hAR-positive tumors with undetectable serum PSA levels were observed, suggesting potential for relapse.
Conclusions:
- hAR expression in prostate cancer following CAB is associated with aggressive tumor characteristics (high-grade, high-stage) and predicts poor remission durability.
- Elevated hAR positivity alongside undetectable serum PSA may serve as a biomarker for predicting relapse after hormonal therapy.