Is the AR-V7 androgen receptor variant a critical key?


In a paper published in the January 1 issue of Cancer Research, it has been suggested that critical distinctions between the hormone receptors of individual prostate cancer patients may explain why some men respond well to hornone therapy and others get only limited benefit. This is not a completely new idea, but authors of this specific paper have put more flesh on the bones of the original hypothesis.

Regular readers of The “New” Prostate Cancer InfoLink will be well aware that prostate cancer cells rely on male hormones called androgens, including testosterone, to survive and grow. Ever since the early discovery of the hormonal dependence of prostate cancer by Huggins and his colleagues, doctors have taken advantage of this dependence to battle prostate cancer by depriving patients of androgens, either by orchiectomy or by pharmaceutical methods. For most patients, this hormone deprivation therapy causes tumors to shrink, sometimes dramatically. However, it’s never a cure — prostate cancer tumors will always, eventually, become resistant to hormonal therapy and start to re-develop as “androgen-independent” or “androgen-resistant” tumors.

Hu et al. used a large database to analyze variations of in the ribonucleic acid (RNA) molecules that prostate cells use to create androgen receptors, eventually identifying seven RNA sequences that are different from the “normal” (wild type) androgen receptor.

When they looked for these sequences in cells isolated from 124 prostate cancer patients, they found over-production of these variants in many prostate cancer cells taken from patients whose disease had become resistant to androgen deprivation therapy. In particular, one variation — now identified as androgen receptor variant 7 (AR-V7), was also prevalent in a group of patients who had never taken hormone therapy, but whose cancer aggressively regrew after surgery to remove their tumors.

The researchers wanted to learn how androgen receptors made from AR-V7 differ from androgen receptors, so under laboratory conditions they forced prostate cancer cells to produce only the AR-V7 sequence. The result? The cells with only AR-V7 receptors acted as if they were continually receiving androgens — “turning on” at least 20 genes that rely on androgens for activation, even though no androgens were present.

It has long been suspected that one of the consequences of hormone therapy might be the selective suppression of hormone-sensitive prostate cancer cells, leading to increased growth and subsequent over-expression of hormone-resistant prostate cancer cells. Hu et al.’s data would seem to suggest the possibilty hormone therapy might encourage prostate cancer cells to overproduce cells carrying the AR-V7 receptor over time, leading them to survive and grow aggressively — even in the absence of androgens. And as Hu and colleagues have shown, AR-V7 receptors are already prevalent in some men prior to the use of hormone therapy, predisposing them to an initially-aggressive form of prostate cancer that doesn’t respond well to androgen deprivation therapy.

To quote the conclusion from the abstract of Hu et al.’s paper, “These results suggest a novel mechanism for the development of [hormone refractory prostate cancer] that warrants further investigation. In addition, as expression markers for lethal [prostate cancer], these novel AR variants may be explored as potential biomarkers and therapeutic targets for advanced [prostate cancer].”

Having said that, let’s bear in mind that these are still early data. There may be more than one androgen receptor that is involved in this process. Much as we might like it to be the case, the simplest solution isn’t always the right solution. It could take a while to validate these data and take appropriate steps to test this theory in clinical practice

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