The androgen receptor gene and its influence on the development and progression of prostate cancer

Abstract

Prostate adenocarcinoma has the highest incidence of any malignancy and is the second leading cause of cancer-related deaths in men in industrialized countries. The development and progression of prostate cancer are dependent on testosterone and dihydrotestosterone; the androgen receptor is the vehicle through which these androgens exert their regulation on prostate cellular proliferation and differentiation. As a result, much effort has been devoted to elucidating the role of the androgen receptor in prostate cancer. The CAG and GGN trinucleotide repeats in exon 1 of the androgen receptor gene have been linked to prostate cancer risk and progression in some studies. Also, androgen receptor gene amplification may be a mechanism of prostate cancer cell adaptation to hormonal therapy. In addition, androgen receptor somatic mutations can result in receptors that have altered binding specificity when compared with wild-type receptors and heightened affinity for hormones other than testosterone and dihydrotestosterone. Gene amplification and somatic mutations, coupled with the fact that various growth factors have been shown to stimulate androgen receptor activity independently of androgens, may enable prostate cancer cells to grow despite testicular-androgen ablation. Unfortunately, current medical therapy for metastatic prostate cancer is deficient, hormone-refractory prostate cancer is a major obstacle in treatment, and, as a result, prostate cancer mortality is still significant. Further study of the function of the androgen receptor will offer a better understanding of prostate cancer pathogenesis and progression, aiding the development of more effective treatments for this disease.

Multi-targeted therapy of cancer by genistein

“…Research on androgens showed that androgens are involved in the development and progression of prostate cancer via activating the androgen receptor (AR) [66]. Prostate-specific antigen (PSA) is a clinically important AR-responsive gene which is used to monitor treatment response, prognosis, and progression in patients with prostate cancer [67].…”

Alleles with short CAG and GGN repeats in the androgen receptor gene are associated with benign endometrial cancer

“…4 Several epidemiologic studies have related the CAG polymorphism with the risk of developing some gynecological and urological, steroid hormone-related tumors, such as breast, ovarian, and prostate cancers, although discrepant results have also been reported. [5][6][7][8] The CAG tract has been associated with some prognostic variables of the above-mentioned cancers and even with the clinical evolution of patients. [9][10][11][12] This suggests that variation in the AR activity promoted by fluctuations in the length of the CAG repeat may affect the progression of tumors as well as influence their development.…”

“…The possible influence of the GGN repeat on the progression of prostate cancer has also been suggested. 8 Endometrial cancer (EC), a steroid hormone-related disease, is the most common pelvic gynecological malignancy in Western countries. 13,14 Most EC develops after the menopause, a physiological condition characterized by a higher androgen-to-estrogen ratio than that present during the fertile period of a woman's life.…”

Androgen Receptor Mutations in High-Grade Prostate Cancer before Hormonal Therapy

“…Somatic AR mutations have been found in only 2% of patients with localized CaP (Marcelli et al, 2000), but the frequency of mutations seems to increase with stage, being the highest in androgenrelapsed metastatic disease (Culig et al, 1993;Montgomery et al, 2001;Taplin et al, 1995;Tilley et al, 1996). We, for example, have reported AR mutations in 27% of the androgen withdrawal therapy and antiandrogen-refractory CaPs (Haapala et al, 2001).…”

“…Preliminary screenings of the whole AR coding sequences from advanced, high-grade CaPs have suggested that AR mutations are frequent in untreated CaP (Koivisto et al, 1998;Montgomery et al, 2001; The Androgen Receptor Gene Mutations Database). Tilley et al (1996) found AR amino acid substitutions in 44% (11/25) of stage C and D 2 CaPs sampled before initiation of hormonal therapy, and Marcelli and co-workers (2000) reported AR mutations in 21% (8/38) of untreated stage D 1 CaPs.…”