Diane Robins
Professor
When a good receptor goes bad
On a personal level, duplicity can be hurtful -- who hasn't been wounded by a two-faced friend? At the molecular level, two-faced behavior also can be devastating, as happens in prostate cancer when the activity of a hormone receptor known as AR changes from helpful to harmful.
Early in life, the male hormone androgen and its partner the androgen receptor (AR) play a key role in normal development of the prostate. But later in life, as genetic errors accumulate leading to the initiation of a tumor, AR turns rogue and begins promoting this abnormal cell growth – cancer – in the walnut-sized gland at the base of the bladder.
Researchers have been looking at differences in androgen receptors and their behavior in different circumstances, hoping to explain their two-faced tendencies. One difference they've discovered is in the length of a region of the receptor called the glutamine tract, says Diane Robins, a professor of human genetics who's exploring the role of the androgen receptor in prostate cancer's initiation, progression and response to treatment.
"It's known from bench science that the longer the glutamine tract, the weaker the androgen receptor, and shorter the tract, the stronger the receptor," Robins notes. "In cancer, it seems reasonable that a stronger androgen receptor might give you a higher risk."
To explore the effect of glutamine tract length on prostate cancer initiation and progression, Robins devised a set of experiments in mice. First her lab group engineered the mice so that their androgen receptors were nearly identical to those of humans; then, going a step further, they made some with short, some with medium and some with long glutamine tracts. The mice all appeared healthy in every way, but they differed from one another in their responses to induced prostate cancer.
"In those with a long tract, tumors started late and grew slowly; in those with a short tract, the tumors started earlier, but they progressed more slowly, so those mice wound up surviving with disease longer than the ones with medium tracts," says Robins. When, in a separate experiment, such mice were treated for prostate cancer, the short tract/strong receptor mice did surprisingly well, surviving longer than the long tract/weak receptor mice, suggesting that the strong receptor might be retaining some normal function within the tumor that helps the mice stay healthier.
Robins stresses that the mouse results can't be directly generalized to humans. For one thing, in both mouse and human prostate cancer, activity of the androgen receptor is influenced not simply by glutamine tract length, but by a whole suite of factors that together make up the “androgen axis.” These factors vary in individual people, but in the lab mice one can vary just one factor at a time. In that way, the mouse model can contribute to the understanding of human prostate cancer and its treatment.
In addition to glutamine tract length, Robins is looking at differences in androgen receptors that arise as mutations as prostate cancer progresses. Her experiments and analyses offer insights into one of prostate cancer's most vexing puzzles: why almost all patients become resistant to treatment and develop even more aggressive tumors.
The usual treatment for prostate cancer involves shutting down androgen production in the testes and blocking activity of the androgen receptor itself in the prostate. Without its hormone partner, the androgen receptor should then be unable to promote cancer growth. But Robins's experiments revealed that certain mutant forms of the androgen receptor can still promote cancer, even in the absence of androgen and despite the binding of the inhibitor.
"Our experiments show the different things that the androgen receptor does at different stages of the disease, and our mouse model can be used to test new drugs targeted at the human androgen receptor," Robins says. "In future work we hope to see what pathways are used in slow progression -- a good response to therapy -- versus aggressive progression, information that may lead to new biomarkers that indicate whether a patient will do well with a given treatment, as well as hopefully identify new targets for drugs to more effectively treat the disease."
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