Androgen signaling is extremely important in the life and death of the prostate gland and is believed to play an important role (s) in prostate cancer. Hormonal therapy, the most common treatment strategy for the treatment of metastatic prostate cancer works by inhibiting androgen signaling. Accumulating evidence suggests that alterations of androgen signaling in prostate cancer may involve structural or functional alterations of the critical genes at numerous points in the pathway. Some of the known examples are illustrated below:
Some of the changes in AR signaling may increase the risk of prostate
cancer whereas others may contribute to the progression of prostate cancer.
Thus, a high throughput assay able to register various alterations of
the androgen signaling pathways is needed to evaluate the role of AR signaling
in prostate cancer onset and/or progression. Following the expression
profile of the downstream targets of the AR may reflect various changes
in the androgen signaling pathways. AR being a transcription factor, the
choice of monitoring the expressional profile of the androgen regulated
genes as a read out of AR functions in prostate tissue represents a logical
and viable approach to define the status of AR signaling in vivo. This
approach also takes into account the possible role of multiple genes affecting
the hormonal pathway, a biologic scenario recently proposed in the genetic
predisposition of prostate cancer.
A unique and novel collection of 500 plus androgen regulated genes (ARGs) form a pool of 25,000 transcripts including known genes, Expressed Sequence Tags (ESTs), and potentially novel genes identified by Serial Analysis of Gene Expression (SAGE) in hormone responsive LNCaP prostate cancer cells. About 10% of the ARGs represent known ARGs and the rest is new information (Xu et al. International Journal of Cancer: 92, 322-328, 2001). The ASRA contains cDNA corresponding to the ARGs identified by SAGE studies and genes known to regulate androgen signaling e.g., genes involved in androgen biosynthesis or metabolism, co-activators or co-repressors of AR and other steroid receptors. Additionally, the ASRA contains genes that exhibit prostate cancer associated alterations. All together the ASRA 1.0 contains about 750 cDNA representing known genes, and ESTs. A patent is pending on ASRA claiming priority to January 2000. Additional ARGs identified in a recent publication (Segawa et al., Oncogene, 21, 8749-8758, 2002) will be added to the next generation of ASRA.
The goal of this new array and its future versions will be to serve as a read-out for androgen signaling status in prostate cancer cells and possibly in other scenarios with some modifications. ASRA 1.0 already has a sufficient number of the known androgen regulated genes to serve as built in internal positive controls.
A short list of possible applications of the ASRA is outlined below:
Included in the array is a newly discovered, novel, prostate abundant,
and androgen regulated gene designated PMEPA1 (Xu et al, Genomics, 66,
257-263, 2000; Xu et al, Cancer Research, 2003) that has been identified
and characterized. PMEPA1 is an androgen regulated gene that exhibits
abundant expression in prostate tissue. The sequence and fragments of
the gene are potentially useful for detecting, diagnosing, preventing,
and treating prostate cancer and other prostate related diseases. PMEPA1
gene has quite intriguing and attractive attributes in the context of
prostate cancer. For example, PMEPA1 may have functions in direct regulation
of the AR and appears to have tumor cell growth inhibitory functions.
Moreover, PMEPA1 may be up regulated by chromosome 8, the most frequent
site of chromosomal deletions in prostate cancer. A patent on PMEPA1 has
been issued (U.S. Patent 6,566,130). Additional patent applications have
been filed on the function and use of PMEPA1 in the treatment of prostate
Similarly, there is further potential to discover other novel hormonally regulated genes from our SAGE and Affymetrix defined ARG database. Our SAGE ARG database has also defined the quantitative profile of almost all of the known potentially new prostate specific genes. This analysis is helping in prioritization of genes for evaluating their utility as biomarkers or therapeutic targets.