| Prostatic carcinoma (PC) is the most commonly diagnosed malignancy in men in the United States and is second only to lung cancer in cancer-related deaths. However, in recent years, with the change of life style, there is also obvious augment of morbidity in our country.Androgens are essential for the development, growth, and maintenance of the prostate. They exert their effects via the intracellular androgen receptor (AP.), which is a ligand-dependent transcription activator. As is the case with normal prostate development, primary prostatic cancers are largely dependent on androgens for growth and survival. Most patients respond favorably to androgen ablation and antiandrogen therapy, which has become a standard treatment of metastatic disease. However, virtually all patients will relapse with clinically defined androgen-independent cancer. This phenomenon raises the question of how cancer cells survive and grow in the low androgen environment? Two of the routes cells can take to adapt are (1) bypassing and (2) sensitizing the AR pathway. The vast numbers of AR abnormalities observed in prostate tumors from patientstreated with hormonal therapy suggest that many cells sensitize or change the AR pathway. To continue to activate this pathway in a low androgen environment, cells can (I) mutate the AR to become promiscuously activated by different steroids, (2) amplify the AR, (3) activate the AR in a ligand-independent manner by growth factors and cytokines, or (4) amplify coactivators. Alternatively, prostate cancer cells that have lost AR expression must have bypassed the AR pathway. Activation of oncogenes and autocrine growth factor stimulation are two mechanisms that likely contribute to becoming completely androgen-independent. From all the studies on AR function in prostate cancer, it is clear that the AR plays an important role in cancer development and progression. Moreover, the AR pathv/ay remains important in most cells from patients with clinically defined androgen-independent prostate cancer.AR like other nuclear receptors displays a modular structure with three main conserved regions: an amino-terminal region harboring an autonomous activation function (AF-1), a centrally located E'NA-binding domain (DBD), and a carboxyl-termirial region containing the ligand-binding domain (LBD) The AR is normally associated with heat shock proteins and in this state cannot bind to androgen-responsive elements). Upon ligand binding, the receptor acquires a new conformational state. Androgen binding induces dissociation from heat shock proteins, hyperphosphorylation, conformational changes, and dimerization of the receptor. This allows binding of the AR to specific DNA sequences called androgen-responsive elements located within the promoters of androgen-responsive genes. In conjunction with cofactor proteins and other transcriptional factors, the AR is then able to up- or down-regulate the transcription of genes, such as C(3), Sip, probasin, PSA, p21 and hKLK2, et.al.The first AR mutation in prostate cancer was described in LNCaP cells several years ago. This mutant receptor binds estrogenic and progestagenic steroids and antiandrogens hydroxyflutamide and nilutamide with high affinity. These substances activate the mutant AR more efficiently than the wild-type one. All mutant ARs detected inprostate cancer that are functionally characterized are "promiscuous" receptors; they can be activated by other steroid hormones arid by nonsteroidal antiandrogens. Subsequently, amino acid substitutions were reported in organ-confined as well as rnetastatic tumors Of the several AR mutants in prostate cancer that have been characterized thus far, the majority are functional and can mediate androgen-induced transactivation, in contrast to loss of function germ-line AR mutations that cause androgen insensitivity.Previous years, in our laboratory, we have identified four missense mutations (G142V, D221H, E872Q, and M886I) in AR from nearly fifty PC samples by PCR-SSCP analysis. However, the effect of these mutati...
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