Prostate cancer cells. Image credit: Public domain
The prostate is a roughly walnut-sized gland that makes up part of the reproductive system in men. The normal development of this gland depends on a protein known as the androgen receptor. This protein also plays an important role in driving the growth of prostate cancers, and doctors routinely treat such cancers with drugs that block the androgen receptor. While these treatments often shrink the tumors at first, the prostate cancer cells commonly become resistant to the existing “antiandrogen” drugs, highlighting the need to find new drugs for this cancer.
The main way that prostate cancers become resistant to antiandrogen drugs is by making more of the androgen receptor. As such, a better understanding of this protein’s activity may prove vital to discovering new treatments. Together with other proteins called co-factors, the androgen receptor binds to DNA and switches on a set of target genes that drive the growth of prostate cancers. The activity of these genes, referred to as “androgen receptor output”, varies between different patients with prostate cancer and even between different cells from a single patient’s tumor. This variation may occur even when the level of the androgen receptor is constant, which suggests that other factors affect the output of the androgen receptor.
Lee et al. set out to discover if cells with different androgen receptor outputs, but constant androgen receptor levels, respond differently to antiandrogen drugs. First, human prostate cancer cells were separated according to their androgen receptor output. Lee et al. then treated all the cells with an antiandrogen drug known as enzalutamide: tumors grown from cells with a high output became resistant to the drug faster than cells with low output. Next, a large-scale experiment revealed the differences in gene activity between cells with high and low outputs. On average, the cells with a high androgen receptor output had more of an androgen receptor co-factor called GREB1 than the cells with a low output. Biochemical experiments showed that the GREB1 protein interacts with the androgen receptor and amplifies the expression of the receptor’s target genes. When the levels of the GREB1 protein were experimentally decreased in prostate cancer cells with a high androgen receptor output, the cells became less resistant to the antiandrogen drug.
Future work will be needed to know if GREB1 levels are a good proxy for patients with high androgen receptor output. The current work predicts that those patients will respond less well to current antiandrogen drugs. A better understanding of how GREB1 and androgen receptor cooperate may also be useful for developing new drugs to treat prostate cancer.
