Abstract
BackgroundAndrogens bind to the androgen receptor (AR) in prostate cells and are essential survival factors for healthy prostate epithelium. Most untreated prostate cancers retain some dependence upon the AR and respond, at least transiently, to androgen ablation therapy. However, the relationship between endogenous androgen levels and cancer etiology is unclear. High levels of androgens have traditionally been viewed as driving abnormal proliferation leading to cancer, but it has also been suggested that low levels of androgen could induce selective pressure for abnormal cells. We formulate a mathematical model of androgen regulated prostate growth to study the effects of abnormal androgen levels on selection for pre-malignant phenotypes in early prostate cancer development.ResultsWe find that cell turnover rate increases with decreasing androgen levels, which may increase the rate of mutation and malignant evolution. We model the evolution of a heterogeneous prostate cell population using a continuous state-transition model. Using this model we study selection for AR expression under different androgen levels and find that low androgen environments, caused either by low serum testosterone or by reduced 5α-reductase activity, select more strongly for elevated AR expression than do normal environments. High androgen actually slightly reduces selective pressure for AR upregulation. Moreover, our results suggest that an aberrant androgen environment may delay progression to a malignant phenotype, but result in a more dangerous cancer should one arise.ConclusionsThe model represents a useful initial framework for understanding the role of androgens in prostate cancer etiology, and it suggests that low androgen levels can increase selection for phenotypes resistant to hormonal therapy that may also be more aggressive. Moreover, clinical treatment with 5α-reductase inhibitors such as finasteride may increase the incidence of therapy resistant cancers.ReviewersThis article was reviewed by Ariosto S. Silva (nominated by Marek Kimmel) and Marek Kimmel.
Highlights
Androgens bind to the androgen receptor (AR) in prostate cells and are essential survival factors for healthy prostate epithelium
We have developed a preliminary model of the binding kinetics of prostate androgens, their relationship to proliferation and death in the prostate epithelium, and the evolution of AR expression, and malignant potential, in different androgen environments
Results using this evolutionary modeling framework have suggested that a low androgen environment caused either by low serum testosterone or clinical intervention with 5α-reductase inhibitors can increase selection for AR overexpression in prostate epithelium, while high androgens may weakly protect against AR overexpression
Summary
Androgens bind to the androgen receptor (AR) in prostate cells and are essential survival factors for healthy prostate epithelium. Finasteride treatment targets the epithelium, with little if any effect seen on the stroma [34], and it dramatically increases the prostate stroma:epithelium ratio [28] Because of their role in protecting against apoptosis and promoting proliferation and the (transient) efficacy of androgen ablation therapy, it has long been thought that high levels of androgens play a causal role in prostate cancer development. In indirect support of this hypothesis, a number of clinical studies have failed to support the notion that high androgen levels increase the risk of prostate cancer [35,36,37,38], and some data suggests that low serum testosterone is associated with aggressive, therapy-resistant tumors. We find that treatment with finasteride (i.e. 5α-reductase inhibition) selects for increased AR expression Together, these results suggest that low androgen environments select more strongly for hormone therapy resistant and possibly more aggressive cancer strains than do normal or elevated androgen environments.
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