By David N. Leff
Men can - rarely - contract breast cancer, but women never get prostate cancer.
In fact, 1 in 100 cases of mammary carcinoma occurs in males, thanks to unisex oncogenic mutations in the BRCA2 breast-cancer susceptibility gene. A somewhat similar gene, BRCA1, inhabits both prostate and female breast cancers.
In women, that same BRCA1 gene, the key culprit in familial mammary and ovarian carcinomas, promotes the nefarious activity of the estrogen hormone's receptor.
"For breast cancer," observed molecular endocrinologist Chawnshang Chang, at the University of Rochester, New York, "we used to believe that estrogen receptor and progesterone receptor are the best diagnostic factors. After a woman has breast cancer surgery, her physician examines whether estrogen or progesterone receptors are positive. If so, then they prescribe hormonal therapy - anti-estrogen tamoxifen [Nolvadex]. But this correlation," Chang added, "is accurate in only about 60 to 65 percent of patients. In other words, for the remaining one-third, even if estrogen is positive, the therapy wouldn't work.
"But with the passage of years," he continued, "physicians found out that if, instead of relying on the estrogen receptor, they used the androgen receptor to monitor, the correlation could be as high as 80 percent. Somehow the androgen receptor shows better correlation to the hormone therapy status of the breast cancer patient, but we still don't know what role that receptor plays in breast cancer." Estrogens drive breast malignancy; androgens (essentially testosterone) plus estrogen, prostate cancer.
Chang is senior author of a paper in the Proceedings of the National Academy of Sciences (PNAS), dated Oct. 10, 2000 (but released Oct. 2).
His article in PNAS bears the title: "Increase of androgen-induced cell death and androgen receptor transactivation by BRCA1 in prostate cancer cells." This paper, he told BioWorld Today, "is the first that links these two important molecules in prostate cancer. One is the androgen receptor (AR), which people currently view as the stimulator of tumor proliferation, or increase. The other molecule, BRCA1, suppresses tumor growth.
"More importantly," Chang observed, "we challenged the classical hypothesis of thinking that if the BRCA1 tumor suppressor gene can help androgen receptor activity, then how are we going to explain these two relationships? And from there we point out that instead of androgen-induced proliferation of the prostate tumor, maybe androgen also contributes to its apoptosis - programmed cell death - by enhancing AR's target oncogene, p21. If so, then we can explain why BRCA1 has androgen receptor activity, because it can enhance this AR by helping its role in apoptosis."
Shifty, Turncoat Hormone Plays Both Sides
Chang described AR's place in current prostate cancer treatment: "To cure a prostate carcinoma, most urologists apply the so-called androgen ablation therapy. But after two years, the tumor goes from androgen-dependent to androgen-independent. And perhaps all this current thinking process views prostate androgen as a stimulant of tumor proliferation. Maybe, in fact, the androgen hormone inhibits it instead."
He made the point that, "If we can think about things the other way, maybe that androgen receptor also stimulates progression of apoptosis in the tumor cells."
In 1988 Chang was the first to clone this androgen receptor gene and publish its complete sequence. He estimates that at least 1,000 papers concerning the molecular biology of the AR have been published in the ensuing decade.
"The androgen receptor," he said, "has become the target of therapeutics focus, because if you want to prevent or stimulate androgen action, you have to deal with its receptor. However," he pointed out, "at this moment, drug development has not been successful because all the anti-androgen receptor inhibitors - such as flutamide (Eulexin), which is currently quite popular - would probably be good clinically for only about 24 months. Roughly after that period, the anti-androgen will become an androgenic compound. That is, it will start to stimulate AR instead of inhibit it. And after that first 24 months of treatment, the drug probably will be dropped, because tumor will recur and will end all further prostate carcinoma hormonal therapy." (See BioWorld Today, Oct. 15, 1996, p. 1.)
Chang's PNAS article reports that BRCA1 - but not p53 - can function oncogenically to interact as a co-regulator to enhance AR activity in prostate cancer cells. "Such co-factors," he suggested, "will provide a good opportunity for next-generation drug discovery to screen new anti-androgen agents in this area. Because instead of trying to find a way to screen against the androgen receptor, now you can screen a compound against the receptor's co-factor. The interaction of the co-activator or co-factor with the receptor is dependent on the androgen hormone itself. That either depends on the androgen, or that hormone will enhance the interaction of these two molecules."
Receptor Sparks Next-Generation Drug Design
"So based on this new principle," Chang said, "if we can screen the new generation of the drug, which can block these two away, that would be helpful. Once the receptor interacts with one molecule, it can either go up or go down. And the basis of this concept is that drugs can be developed to block the interaction between these two molecules." (See BioWorld Today, May 12, 1998, p. 1.)
So far, his experiments have all been in vitro assays. "Instead of using animal or human material," he recounted, "we employed the cell culture system to demonstrate that AR activity can be enhanced when you add the BRCA1. So we had to put the gene in, and pull the gene out, to monitor the receptor activity.
"In vivo experiments," he foresees, "should be a few years off, awaiting the eventual creation of a suitable AR knockout mouse. That would enable us to see just how important the BRCA1 really is.
"Meanwhile," he added, "I think it's about time industry put more effort into developing a pure anti-androgen that will not turn into an agonist later on as we treat the patient - after 20 or 24 months. It's about time," Chang concluded, "because so far there is no cure for this so-called hormone-dependent prostate cancer or breast cancer."