Role of androgen in prostate cancer

Even with these "hard wiring" changes, activation of these pathological growth-promoting (i.e., oncogenic) pathways can still be dependent upon the binding of androgen to its receptor in the nuclei of these neoplastic cells themselves (i.e., androgen and AR-dependent), or they can be constitutive (i.e., independent of the binding of physiological androgens to the receptors), but still requiring AR functioning in the nuclei of these malignant cells to enhance the transcription of both secretory markers and also growth-promoting genes, (i.e., androgen independent but still AR dependent).

In order to appreciate the therapeutic relevance of these mechanistic distinctions, an understanding of the cellular heterogeneity and responsiveness of prostate cancer cellular subtypes is required. Androgen ablation therapy, whether by surgical or medical means, induces the elimination of only testosterone-dependent prostate cancer cells since these cells require a critical level of physiological androgen for their continuous proliferation and survival (Gao and Isaacs 1998; Gao etal. 2001; Kyprianou etal. 1990). Unfortunately, androgen ablation is not curative because, once clinically detected, prostate cancers are heterogeneously composed of clones of androgen-dependent cancer cells and also malignant clones which are androgen-independent (Isaacs 1999). These latter cells are androgen-independent since androgen occupancy of their nuclear AR is not required for their survival (Isaacs 1999). There are two basic subtypes of such androgen-independent prostate cancer cells. One subtype retains a sensitivity to androgen occupancy of its nuclear

AR to enhance its rate of cell proliferation even though such occupancy is not required for its survival. Thus, these cells are androgen-independent/sensitive since their rate of growth is inhibited but not prevented by androgen ablation. The other subtype is termed androgen independent/insensitive since androgen ablation decreases neither their rate of proliferation nor survival (Isaacs 1999).

These last two subtypes of malignant clones are not eliminated by standard androgen ablation and thus these are the malignant cells that eventually kill the patient (Isaacs 1999). It had been assumed that following androgen ablation, such androgen-independent/insensitive prostate cancer cells no longer express androgen receptor and that in such androgen-independent/sensitive cells, the expressed AR had no function in regulating survival. This assumption was based upon earlier observations that the majority of serially passaged rodent and human (i.e., PC-3, DU-145) in vitro cell lines established from androgen ablation-failing hosts consistently did not express AR. In contrast to this experimental situation, more than 90% of prostatic cancers obtained directly from patients failing androgen ablation actually overexpress AR (Hobisch et al. 1996; Linja etal. 2001; Taplin et al. 1999). In approximately 30% of such progressing prostatic cancer, this overexpression is associated with genetic amplification (Brown et al. 2002; Hyytinen et al. 2002) and, in 10-40%, with AR mutations (Buchanan et al. 2001; Hyytinen et al. 2002; Taplin etal. 2003). These clinical results strongly implicate continual involvement of AR in stimulation of proliferation and/or inhibition of death even in ligand (i.e., androgen) independent prostate cancer cells resistant to androgen ablation. This is supported by a growing body of experimental studies using prostate cancer model systems which have documented that manipulations which interfere with AR expression, nuclear translocation, and/or appropriate genomic binding inhibit proliferation and induce apoptosis of ligand-independent (i.e., androgen ablation resistant) AR expressing prostatic cancer cells (Chen et al. 1998; Eder et al. 2002; Zegarra-Moro etal. 2002). Thus, targeted inhibition of these ligand-independent-AR signaling pathways should provide rational drug development for androgen ablation resistant prostatic cancers (Litvinov etal. 2003).

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