Dihydrotestosterone (DHT), the 5a-reduced product of testosterone, binds to androgen receptors with 2.5-fold higher affinity than testosterone itself, and serves as the major regulator of prostatic tumor growth. Androgen-mediated cancer proliferation occurs by direct effects of androgens, indirectly by growth factors stimulated by androgens, and by a combination of these mechanisms.66 Approximately 7000 mg of testosterone is secreted daily by the testes of which only 7% is converted into DHT in peripheral tissues.66 The testes produce 95% of androgens in men, while the adrenal gland accounts for the remaining 5% of hormone.67 Testosterone, as well as precursors to androgens, such as androstenedione, dehydroepiandrosterone (DHEA) and DHEA sulfate, originate in the adrenal gland and are likewise converted to DHT in peripheral tissues. Approximately 40% of prostatic DHT originates from steroids of adrenal origin.68 Androgen-dependent prostate cancer contains androgen receptors that bind DHT and transmit proliferative signals to the nucleus.69
The responsiveness of the prostate gland and most prostate cancers to androgen indicates the importance of this hormone, as well as the ability to manipulate its action, in prostate cancer treatment. Many abnormalities in AR expression occur during prostate cancer progression and the AR gene is amplified in 30% of hormone refractory prostate cancers and multiple copies of chromosome X are found in 20% of such tumors.70'71 Additionally, mutations of the androgen receptor occur, but the frequency in primary prostate cancer is controversial.72 An early study found a 30% incidence of androgen receptor mutations in primary prostate cancers, while others have found a much lower frequency ranging from 0% to 5%. However, all investigators find mutations in metastatic disease ranging from 21% to 50%.73 The frequency and type of mutations appear to be influenced by selective pressure exerted by antiandro-gens.74 As previously discussed, these mutations may be the reason we see the flutamide withdrawal response.75 Drawing a parallel with breast cancer, in which estrogens are known to play an important role and the antiestrogen tamoxifen has been shown to decrease risk, the Prostate Cancer Prevention Trial (PCPT) is studying 18000 men to determine if the 5a-reductase inhibitor finasteride will effect the development of clinically significant prostate cancer.76,77 In time, the PCPT should provide insight regarding the efficacy of finasteride on preventing invasive prostate cancer.
In contrast to breast cancer, where estrogen receptor (ER) and progesterone receptor (PR) expressions are lost in hormone refractory disease, AR mRNA is upregulated in vitro in androgen-independent prostate cancer cell lines.78 Furthermore, in vivo studies have demonstrated high levels of AR expression as well as increased expression of androgen-regulated genes in castrate versus hormonally intact human prostate cancer xenografts.79 The maintenance of androgen-regulated genes in the absence of androgen could occur via an AR-independent mechanism; however, the importance of androgen-independent activation of AR itself is becoming increasingly recognized. In the absence of androgen, cytosolic AR can be phosphorylated and activated by alternative kinase pathways. For example, the protein kinase A (PKA) activator, forskolin, was shown to activate AR in vitro in the absence of androgen; this effect could be blocked by a PKA inhibitor protein and partially blocked by the competitive inhibitors flutamide and bicalutamide. The authors demonstrated that AR activation in this manner is dependent on a functional AR DNA-binding domain by mutational studies.80 Other studies have shown androgen-independent activation of AR involving mitogen-activated protein (MAP) kinase, HER-2/neu receptor tyrosine kinase and cyclin-dependent kinases.81-84 A separate mechanism of androgen-independent AR activation occurs through direct binding of growth factors to cytosolic AR. As previously mentioned, IGF-1, KGF and EGF all are capable of activating the AR in the absence of androgen.21 FGF-1 and FGF-2 however, were shown to lack this ability in vitro.115 Interestingly, blockade of the EGF receptor stimulated pathway with the specific inhibitor of PKA (H89) in DU145 cells was found to inhibit not only the action of EGF on the MAP kinase system, but also IGF-1 activation of MAP kinase as well as the interaction between the kinase pathways PKA and MAP kinase.86 PKA pathway inhibition with H89 in DU145 cells has also been shown to abolish the neuropeptide calcitonin, which is secreted in neuroendocrine variants of androgen-independent tumors, mediated activation of MAP kinase.87 Similarly, the epidermal growth factor receptor (HER)-2/neu inhibitor tyrphostin AG825, a cell-permeable tyrosine kinase inhibitor, preferentially induced apoptosis in androgen-independent C4-2 cells but not androgen-dependent LNCaP cells.88 This complex and convergent activation of AR, along with mutations in AR that allow activation by antiandrogens, likely plays an important role in androgen-independent mitogenic stimulation by AR in hormone refractory disease. Strategies inhibiting AR activation in the absence of androgen could be utilized to reduce autonomous tumor growth. A monoclonal antibody against AR has been developed (F52.24.4) against the C-terminal portion of the DNA binding domain.89 It may be possible that disruption of AR interaction with DNA by such an antibody could inhibit the penultimate step in AR-responsive genes. Similarly, any strategy to knockout AR in hormone-independent prostate cancers may prove to alleviate the mitogenic stimulus by AR in these cancers. Otherwise, delineating the relative importance of the aforementioned mechanisms of AR activation could narrow the approach to designing treatment alternatives.
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