The Androgen Receptor
Â Â The Androgen Receptor (AR) is a protein inside of certain cells that can bind or capture the androgen hormones testosterone and the more active metabolite 5alpha-dihydrotestosterone (DHT). Once the receptor binds one of the hormones, it causes the receptor to become active and stimulate production of certain proteins inside cells such as PSA.
It is known that AR is required for the normal development of the prostate. If a male animal has no AR, then the prostate will not be created of will be very small when he is born.
The AR is very important for normal maintenance in the prostate as well. Once the prostate has developed in adulthood, androgen hormones serve to keep secretory epithelia cells in the prostate alive. It should be noted that secretory epithelia is thought to be the main cell type that is responsible for prostate adenocarcinomas. These cells are also thought to produce and secrete growth factors that further stimulate growth of cells.
ARâ€™s role in prostate cancer
Â Â There have been over 45 mutant or abnormal ARs characterized from prostate cancer patients. Most of these mutations allow the AR to become active even from binding other hormones and molecules besides DHT and testosterone. This is thought to be one of the main problems in prostate cancer since the AR is consistently active and would promote uncontrolled growth within the prostate. It has been shown that increased androgens in the body (such as those taking steroids) do not correlate with increased prostate cancer rates, but do correlate with increased prostate growth.
Prognosis and response
Â Â One way to rate prostate cancer is through its microscopic appearance termed a Gleason score. The higher this score is, the worse the prognosis. A higher score indicates the prostate glands have become malformed and there is no real structure, just loosely packed sheets of cells.
Â Â Another prognostic marker in prostate cancer is PSA (prostate specific antigen) levels in the blood. PSA is actually a protein that normally functions in breaking down or cutting up other proteins (termed a protease). PSA is usually secreted into the glands or ducts of the prostate from the prostate cells. When these ducts become malformed, indicated by a higher Gleason score, the leakage of this protein into the blood becomes more prevalent. This leakage can then be monitored to determine progression of the prostate cancer as well as treatment response. Less cells or less proliferation coincides usually with less PSA in the serum.
Â Â Since prostate cancer cells are thought to mainly depend on the AR for proliferation and continual progression, the current treatments aim toward hormonal or surgical treatment (also called biochemical treatment) to target AR instead of direct chemotreatment (treatment with synthetic usually unnatural molecules) which target various molecular pathways within the cell. The main goal of treatment is to get rid of the hormones that signal the AR and keep the secretory epithelial cells in the prostate alive. One way to do that is to block luteinizing hormone-releasing hormone (LH-RH) with an agonist. This will stop the testes from releasing testosterone. No testosterone means no DHT, no AR activation and the death of secretory prostate epithelia. Some LH-RH agonists include leuprolide (Lupron) or goserelin (Zoladex). Another hormone treatment can be through anti-androgenic drugs such as flutamide (Eulexin) or bicalutamide (Casodex) which will act to stop the AR activity directly. And there is also castration, which removes the testes, or prostatectomy which removes the prostate altogether.
Hormone Refractory cancer, metastasistermterm and selected treatments
Â Â When hormone treatments fail to stop the progression of the prostate cancer, it is said to hormone refractory and androgen independent. That is, the prostate cancer no longer responds normal to anti-androgen hormones and keeps growing. One theory on what is happening in the hormone refractory cancer cells is the AR has become mutated.
Â Â It has been shown that in some cases the AR is mutated in 21-44% of metastaticterm tumors from prostate cancer patients. It has also been shown that prostate cancer cells have AR throughout the progressive stages of the disease. It is shown that the most common mutations in AR allow the protein to become activated by other hormones and even the anti-androgens. This is why hormone therapy is usually stopped, since it is now thought the anti-hormones have started to activate growth in the prostate instead of inhibiting it. The other hormones that can activate the mutant AR include adrenal androgens. These adrenal androgens are why in some treatment plans the adrenal suppressants Ketoconazole or aminoglutethimide (both aromatase inhibitors) are given to stop production of these potential activators of the mutant AR.
Â Â With metastatic cancers, the treatment regimes usually turn toward chemotherapyterm or radiation, with or without hormone therapy. Note, most chemotherapy is non-specific in the sense that they affect all cells, not just cancer cells. The rationale for most of these therapies seems to be cancer cells are more susceptible to these drugs since they are proliferating faster than normal. The side effectsterm are from the drugs altering or killing normal functioning cells.
Â Â The following are a few common chemo drugs used to treat prostate cancer. Docetaxel, also known as TaxotereÂ®, is an antimicrotubule agent which causes stabilization of the cells internal supporting scaffolding ultimately preventing cell division and proliferation. Mitoxantrone is an intercalating agent which inserts in between DNA or RNA disrupting their synthesis which eventually leads to cell death.
Â Â With bone metastases, radiopharmaceuticals can be used. Strontium-89 is a radioactive element that accumulates in the bone. The radiation given off by this element destroys proteins and DNA leading cellular death. Other non-radioactive drugs can be used to treat bone metastases. Bisphosphonates (some include etidronic acid [DidronelÂ®] and alendronate [FosamaxÂ®]) are used to stop normal bone reformation which would prevent new growth from bone metastasis.
Â Â While it seems AR is very important in the progression and development of prostate cancer, new therapies are emerging that go against the traditional hormone therapy as a first treatment. Instead, these new therapies, which are in clinical trials, use chemotherapy before hormone treatment. The new trial therapies for prostate cancer are different, and may take a while to be proven clinically.
An excellent AR review, which was gleaned for most of this article, is in Endocrine Review 25(2):276-308. Androgen Receptor in Prostate Cancer.