Researchers identify a link between androgen receptor activation and cancer invasiveness, metastasis.
Activation of the androgen receptor (AR) appears to promote the invasiveness of both androgen-dependent and androgen-refractory prostate cancer, data suggest.
In addition, a more invasive phenotype might develop through AR activation during cancer progression, according to researchers in California. They say their new findings support the use of adjuvant hormonal therapy and the future development of more potent androgen blockade therapy.
Until now, the role of AR in invasion/metastasis has not been well established. Nor has the relationship between invasiveness and androgen-refractory status been well established. Now, investigators at the Jonsson Cancer Center at the University of California in Los Angeles (UCLA) for the first time have found a connection between the activation of AR and the spread of prostate cancer as well as the progression to androgen independence.
Previous studies have shown that the androgen receptor is responsible for the growth of hormone refractory prostate cancer, but no one has associated the spread of prostate cancer to the androgen receptor.
“We started noticing that the castration-resistant prostate cancer models in the lab seemed to express genes that are typically associated with the spread of cancer,” said senior study author Robert Reiter, MD, professor of urology at UCLA. “We began to ask what cell signaling pathways might be responsible. We looked at the androgen receptor and were surprised to find that it was not only overexpressed in castration resistant cancers but also in invasive cancers that still relied on androgen to grow.”
The study, which appears in Cancer Research (2008;68:1-9), found that overexpression of the AR was critical to the cancer becoming more invasive. If a therapy could be found that blocked overexpression of the receptor, then it might be possible to stop the spread of certain prostate cancers, Dr. Reiter said.
Although clinicians frequently try to delay treatment with hormonal therapy due to its harsh side effects (hot flashes, osteoporosis, and sexual dysfunction), these new study findings support the concept of starting hormonal therapy earlier rather than later in the course of the disease,
Dr. Reiter said.
“Early hormone treatment in this group of men might allow them to live longer,” Dr. Reiter said. “High levels of androgen receptor in the primary tumor might also predict which cancers are more likely to spread despite initial surgery or radiation.”
This strategy could be particularly effective in high-risk men, such as those with large primary tumors, high Gleason scores, or lymph node involvement at diagnosis. He and his colleagues say there may be one caveat to this approach: Early hormonal therapy may speed development of hormone-refractory disease, which could be more invasive than untreated disease.
The researchers say the tradeoff of early inhibition of invasion compared with earlier development of more invasive hormone-refractory prostate cancer needs to still be further examined in animal models.
“I would not change my clinical behavior based on a basic science paper, but the paper provides a rationale for why there appears to be clinical benefits with early hormonal therapy,” Dr. Reiter told Renal & Urology News.
“The most important take-home message is that the androgen receptor may be responsible for prostate cancer growth but also prostate cancer invasion and metastasis.”