Prostate cancer stem cells: the role of androgen and estrogen receptors

Abstract

Prostate cancer is one of the most commonly diagnosed cancers in men, and androgen deprivation therapy still represents the primary treatment for prostate cancer patients. This approach, however, frequently fails and patients develop castration-resistant prostate cancer, which is almost untreatable.Cancer cells are characterized by a hierarchical organization, and stem/progenitor cells are endowed with tumor-initiating activity. Accumulating evidence indicates that prostate cancer stem cells lack the androgen receptor and are, indeed, resistant to androgen deprivation therapy. In contrast, these cells express classical (α and/or β) and novel (GPR30) estrogen receptors, which may represent new putative targets in prostate cancer treatment.In the present review, we discuss the still-debated mechanisms, both genomic and non-genomic, by which androgen and estradiol receptors (classical and novel) mediate the hormonal control of prostate cell stemness, transformation, and the continued growth of prostate cancer. Recent preclinical and clinical findings obtained using new androgen receptor antagonists, anti-estrogens, or compounds such as enhancers of androgen receptor degradation and peptides inhibiting non-genomic androgen functions are also presented. These new drugs will likely lead to significant advances in prostate cancer therapy.

Keywords: GPR30, stem cells; androgen receptor; estradiol receptors; prostate cancer.

Figure 1. Model of androgen action in target cells

The transcriptional and non-transcriptional models of androgen action in target cells are depicted. Upon ligand binding, cytoplasmic AR dimerizes and translocates into nuclei of target cells, where it activates gene transcription [1, 4, 24, 80]. In the extra-nuclear compartment of target cells, ligand-bound AR recruits and activates various signaling effectors, including Src, PI3-K, β1-integrin and filamin A. Stimulation of target cells with androgens triggers cell cycle progression through AR/Src/PI3-K complex assembly [28, 31]. Androgens also induce the assembly of AR/filamin A/β1-integrin complex. This complex activates Rac, thereby inducing motility or differentiation in target cells [29, 30]. Under certain conditions, the androgen-triggered AR/filamin A complex activates the Rac/dual-specificity tyrosine-phosphorylation regulated kinase 1B (DYRK1B) pathway, leading to p27 Ser10 phosphorylation and p27 stabilization. Reversible quiescence of target cells follows [37]. By this mechanism, androgens might offset the growth-promoting functions driven by oncogenic Ras [37] or growth factors (unpublished results).

Figure 2. Function of AR and ERs in PC epithelial cells and prostate SCs

Panel A illustrates the putative role of AR and ERs (α or β) in epithelial PC cells. Depending on experimental setting, these receptors mediate the indicated biological responses in PC cells [27]. Panel B illustrates the putative role of AR and ERs (α or β) in prostate SCs or CSCs. With few exceptions [103], AR is almost undetectable in prostate and PC SCs [8, 11-15, 93-95]. Prostaspheres derived from primary human prostate epithelial cells express ERs (α or β1) that activate transcriptional and non-transcriptional mechanisms, thus sustaining growth, transformation and stemness [12, 15, 102]. PC epithelial cells and prostaspheres derived from primary human prostate epithelial cells also express the novel ER, GPR30 [12, 15, 85, 86].