Abstract
BackgroundThe exact relationship between hormonal activity and prostate cancer(PCa) has not yet been clearly defined. One of the key hormones associated with PCa is testosterone(T). However, both in vitro and in vivo studies have shown that under some conditions T is capable of either promoting PCa growth or death. This article proposes a theory which resolves this apparent paradox.ModelThe Estradiol-Dihydrotestosterone(E-D) model introduced in this paper proposes that 17β-estradiol(E2) is essential for initiating the growth of PCa cells through the formation of telomeres. It also proposes that T is responsible for increasing the expression of proteins which cause apoptosis, or programmed cell death, and that 5α-dihydrotestosterone(DHT) is essential for preventing this. In addition, it is known that some T is converted to both E2 and DHT, which means that depending on the conditions, T is capable of either promoting the growth of or the killing of PCa.
Highlights
The exact relationship between hormonal activity and prostate cancer(PCa) has not yet been clearly defined
This increase is negated by the addition of 4-hydroxytamoxifen(OHT). It is known[11] that OHT acts as an antagonist to ER-α. All of this is consistent with the hypotheses of the E-D model that E2 increases the production of bcl-2 when binding to ER-α and decreases it when binding to estrogen receptor-β (ER-β)
This indicates that T binding to iAR is not able to completely prevent the apoptosis induced by T binding to mAR, whereas DHT is. This can be represented symbolically as T:mAR >>> T:iAR in the presence of F and DHT:iAR >>> T:mAR in the absence of F. This is consistent with the hypothesis of the E-D model that DHT is essential for initial PCa growth because it protects the PCa from mAR induced apoptosis
Summary
There are currently two models for prostate cancer(PCa) which are diametrically opposed to each other. All of this is consistent with the hypotheses of the E-D model that E2 increases the production of bcl-2 when binding to ER-α and decreases it when binding to ER-β It has been shown[12] that T binds to mAR to produce apoptosis by upregulating the protein Fas. In the PCa cell line DU145 which lacks iAR, T or DHT alone was sufficient to induce apoptosis. This is consistent with the hypothesis of the E-D model that DHT is essential for initial PCa growth because it protects the PCa from mAR induced apoptosis It is known[1] that men with a genetic mutation that produces non-functional 5AR2 do not get PCa. Since 5AR2 is found within the prostate cells and converts T to DHT, the result is very little DHT in the prostate. This is consistent with mAR being involved in the upregulation of bcl-2 and iAR being involved with the down-regulation of bcl-2, as proposed in the E-D model
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