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Review
. 2015 Jan-Feb;39(1):17-28.
doi: 10.1016/j.currproblcancer.2014.11.004. Epub 2014 Nov 25.

The biology of castration-resistant prostate cancer

Fei Lian, Nitya V Sharma, Josue D Moran, Carlos S Moreno
Review

The biology of castration-resistant prostate cancer

Fei Lian et al. Curr Probl Cancer. 2015 Jan-Feb.
No abstract available

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Figures

Figure 1
Figure 1. Signaling Pathways in Castration Resistant Prostate Cancer
(A) TGF-β pathway is stimulated via TGF-β induced receptor complex activation, leading to phosphorylation of SMAD2/3 and subsequently form a trimer with SMAD4 and translocate to the nucleus and associate with other transcription factors to transcribe SOX4 which activates EZH2 expression leading to EMT. (B) Prostate cancer cells depend on the androgen receptor (AR) pathway and steroid hormones for continued oncogenic growth. This can occur by way of AR over expression or by AR gene amplification. Mutations in AR allow binding and activation of AR by other steroidal hormones. Wnt pathway genes are frequently mutated in CRPC and are transcriptional targets of AR. (C) Activation of the PI3K-AKT-mTOR pathway is extremely common in CRPC. Activated growth factor receptor tyrosine kinases (e.g. EGFR and IGF-1R) leads to activated PDK1, which in turn activates AKT. AKT separately phosphorylates and activates mTOR which promotes cell cycle progression, protein synthesis and decreased apoptosis. AKT can interact with AR in an androgen independent manner. (D) Activation of Receptor Tyrosine Kinase (RTK) pathway (PDGFR, HGFR/c-MET, etc) leads to proliferation through RAS-MAPK. Combined with loss of PTEN, overactive RAS-MAPK can induce EMT. (E) Intratumoral synthesis of steroidal hormones from cholesterol via upregulation of the cytochrome P450 gene CYP17A1. (F) Loss of the PTEN Tumor Suppressor promotes aberrant PI3K-AKT-mTOR signaling. (G) Aberrant Y534 phosphorylation by Src increases AR sensitivity to androgens. (H) Epigenetic Pathways: Hypermethylation of CpG islands in gene promoters inhibits expression of tumor suppressor genes or miRNAs targeting AR.
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