Increased expression of androgen receptor (AR) and enzymes in metastatic PCa
Tuesday, 26 May 2009- Androgen receptor (AR) signalling remains active in castration-resistant prostate cancer (CRPC) despite castrate levels of circulating androgens. This is indicated by continuous expression of androgen-responsive genes and is due to mechanisms that include: increased AR expression; AR mutations allowing promiscuous activation by alternative ligands; and increased intratumoural androgen levels, resulting from in situ steroidogenesis.
A group of US researchers examined AR expression and will present their findings at the forthcoming ASCO Annual Meeting to be held in Orlando, Florida, from 29 May to 2 June.
In the study, gene expression profiles of 30 normal prostate tissue samples, 131 primary prostate carcinomas (PCas) and 16 metastatic PCas, generated using Affymetrix Exon arrays, were interrogated for levels of 40 mRNAs encoding AR, SHBG, 28 enzymes involved in androgen synthesis and 10 enzymes involved in androgen inactivation. For individual tumours, a transcript was considered to be overexpressed or underexpressed when its levels were >2 SDs higher or lower, respectively, than its average levels in normal tissue.
The results showed that metastatic PCas expressed higher average transcript levels for AR and several steroidogenic enzymes, including SRD5A1 and SRD5A3, than primary PCas and normal prostate tissue. Expression of SRD5A2, CYP3A4, CYP3A5, and CYP3A7 mRNAs was decreased both in primary and metastatic tumors compared to normal prostate tissue.
In analysis involving AR and 28 steroidogenic transcripts in individual tumours, all (16/16) metastatic PCas overexpressed at least one transcript (range: 2-14, median: 5 transcripts) compared to normal tissue, while 100/131 (76%) primary PCas overexpressed at least one transcript (range: 2-16, median: 2).
"Metastatic PCas overexpress AR and several steroidogenic enzymes, while they express lower levels of the androgen-inactivating enzymes CYP3A4, CYP3A5, and CYP3A7. These data highlight the role of AR and the androgen synthetic pathway as a therapeutic target in CRPC," the authors wrote.
They added that novel antiandrogens (MDV3100) and CYP17 inhibitors (abiraterone) are already in clinical trials in CRPC. Overexpression of AR or steroidogenic enzymes may serve as a biomarker (e.g. by detection via RT-PCR in circulating tumor cells) to predict for sensitivity to these agents and guide patient selection for participation in clinical trials.
Source: N. Mitsiades, N. Schultz, B. S. Taylor, et al., Prostate Cancer Genome Project Group; Memorial Sloan-Kettering Cancer Center, New York, NY, "Increased expression of androgen receptor (AR) and enzymes involved in androgen synthesis in metastatic prostate cancer: Targets for novel personalized therapies," Abstract 5002, Session on Signal Transduction Pathways in Prostate Cancer, American Society of Clinical Oncology (ASCO) Annual Meeting, Orlando, Florida, USA, May 29-June 2, 2009.