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Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer
M E Taplin1, G J Bubley, T D Shuster
1Department of Medicine, University of Massachusetts Medical Center, Worcester, USA.
Background:
Metastatic prostate cancer is a leading cause of cancer-related death in men. The rate of response to androgen ablation is high, but most patients relapse as a result of the outgrowth of androgen-independent tumor cells. The androgen receptor, which binds testosterone and stimulates the transcription of androgen-responsive genes, regulates the growth of prostate cells. We analyzed the androgen-receptor genes from samples of metastatic androgen-independent prostate cancers to determine whether mutations in the gene have a role in androgen independence.
Methods:
Complementary DNA was synthesized from metastatic prostate cancers in 10 patients with androgen-independent prostate cancer, and the expression of the androgen-receptor gene was estimated by amplification with the polymerase chain reaction. Exons B through H of the gene were cloned, and mutations were identified by DNA sequencing. The functional effects of the mutations were assessed in cells transfected with mutant genes.
Results:
All androgen-independent tumors expressed high levels of androgen-receptor gene transcripts, relative to the levels expressed by an androgen-independent prostate-cancer cell line (LNCaP). Point mutations in the androgen-receptor gene were identified in metastatic cells from 5 of the 10 patients examined. One mutation was in the same codon as the mutation found previously in the androgen-independent prostate-cancer cell line. The mutations were not detected in the primary tumors from of the two patients. Functional studies of two of the mutant androgen receptors demonstrated that they could be activated by progesterone and estrogen.
Conclusions:
Most metastatic androgen-independent prostate cancers express high levels of androgen-receptor gene transcripts. Mutations in androgen-receptor genes are not uncommon and may provide a selective growth advantage after androgen ablation.
Insights
Mutations in the androgen receptor gene are common in metastatic prostate cancer, contributing to treatment resistance. These genetic changes may drive the growth of androgen-independent tumors after initial therapy.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Metastatic prostate cancer is a significant cause of cancer-related death in men.
- While androgen ablation is initially effective, most patients develop resistance due to androgen-independent tumor growth.
- The androgen receptor (AR) plays a critical role in prostate cell growth by mediating testosterone's effects.
Purpose of the Study:
- To investigate the role of mutations in the androgen receptor gene in the development of androgen-independent metastatic prostate cancer.
- To determine if genetic alterations in the AR gene contribute to treatment resistance.
Main Methods:
- Synthesized complementary DNA from metastatic prostate cancer samples of 10 patients.
- Estimated androgen receptor gene expression using polymerase chain reaction (PCR).
- Cloned and sequenced specific exons of the androgen receptor gene to identify mutations and assessed their functional effects in transfected cells.
Main Results:
- All androgen-independent tumors showed high androgen receptor gene transcript levels.
- Point mutations in the androgen receptor gene were found in 5 out of 10 patients with metastatic disease.
- Functional analysis revealed that some mutant androgen receptors could be activated by progesterone and estrogen, unlike the wild-type receptor.
Conclusions:
- High expression of androgen receptor gene transcripts is characteristic of most metastatic androgen-independent prostate cancers.
- Mutations in the androgen receptor gene are frequently observed and may confer a growth advantage, leading to resistance after androgen ablation therapy.