The androgen receptor and CaP progression

The development and progression of prostate cancer (CaP) is largely dependent on the dysregulation of the androgen/androgen receptor (AR) signaling pathway; though, the mechanism of CaP progression remains elusive. Initial treatments for CaP included prostatectomy or radiation to destroy cancerous cells [1]. However, these treatments were not curative and more often than not there were recurrences and metastases of the cancer. Mainstay treatments that target the androgen/AR pathway through anti-androgen and androgen ablation therapies have been promising; yet again, these therapies seem to fail as the tumor progresses. This suggests that the androgen/AR dependence of CaP cells vary over time such that alterations in androgen availability, AR sensitivity and receptor promiscuity fuel a more aggressive CaP.

Approximately 80-90% of CaPs are originally androgen dependent (AD) at diagnosis [2]. Androgens stimulate the proliferation and inhibit the apoptosis of cells, thus implicating that CaP cells require a certain level of androgens to maintain their proliferation and survival [1]. This is primarily the reason why androgen ablation therapy is initially successful—it removes the stimulation these cells require for proliferation, ultimately causing the regression of the tumor. However, over time patients often fail androgen ablation therapy as the tumor becomes a more lethal androgen independent (AI) or castration resistant form. There is no effective therapy for AI-CaP.

The prostate requires androgenic steroids for development and function. Testosterone is the main circulating androgen and is secreted from the testes as well as the adrenal glands (adrenal steroid conversion). Once in the blood stream, the majority of the testosterone binds to albumin and sex-hormone-binding globulin (SHBG) while a small fraction is freely dissolved within serum. Within the prostate, testosterone is converted to a derivative, dihydrotestosterone (DHT), by 5-alpha-reductase. DHT is a more potent and active form of testosterone and has a greater affinity for the AR relative to testosterone. Testosterone and DHT bind to the AR and causes its nuclear localization, transcriptional activation and its interaction with co-regulators/ co-activators to mediate AR-directed gene transcription [2].

The AR is required for the development of prostate carcinogenesis from early prostate intraepithelial neoplasia (PIN) to organ-confined or locally invasive primary tumors [3]. As a member of the steroid-thyroid-retinoid nuclear receptor superfamily of proteins, the AR is in its inactive form within the cytoplasm, bound to heat shock proteins (HSP) [4-7] and components of the cytoskeleton [7,8], preventing AR nuclear localization and transcriptional activation. The binding of DHT or testosterone causes a conformational change leading to the dissociation of the AR from the HSPs and its subsequent phosphorylation [1, 9]. Once ligand bound, the AR is stabilized within the cytoplasm and translocates to the nucleus. The androgen-AR complex is in a conformational state to now homodimerize within the nucleus and bind to androgen response elements (AREs) in the promoter region of target genes [1] such as prostate specific antigen (PSA), a routine biomarker for prostate cancer diagnosis and progression [7, 10] and, probasin, a prostate-specific gene that has been exploited as a marker of prostate differentiation [11]. The AR has both a cytoplasmic and nuclear distribution, and shows a certain degree of trafficking either to or from the nucleus [12]. There are varying reports on the subcellular distribution of the AR in different cell types; however, this two-step model for steroid hormone receptor activation is a clear representation of ligand activated translocation and the observed focal accumulations of the AR within the nucleus [12].

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