Expression of suicidal genes in prostate cancer cells using prostate-specific promoter and enhancer elements as well as targeting of the androgen receptor or the insulin-like growth factor genes with triplex technology in prostate cancer cells and their metastases, is expected to be of therapeutic value.
The role of androgen receptor (AR) mutations in androgen-independent prostate cancer (PCa) was determined by examining AR transcripts and genes from a large series of bone marrow metastases.
The progression from low-grade to high-grade prostate carcinoma and metastases is mediated by a selective down-regulation of the androgen receptor target genes that inhibit proliferation, induce differentiation, or mediate apoptosis.
These results suggest that, similarly to Snail and Twist, the activated AR can downregulate E-cadherin expression to promote the activation of epithelial-mesenchymal transition and tumor metastasis.
The mean AR density in the hot spots of different histological areas within the same sections were compared and the correlation of malignant epithelial AR density with clinicopathological parameters such as Gleason score, tumor, nodes and metastases (TNM) stage and pre-treatment prostate-specific antigen (PSA) value was assessed.
To validate this hypothesis, we compared AR variants in metastases obtained by rapid autopsy of patients treated with flutamide or bicalutamide, or by excision of lymph node metastases from hormone-naïve patients.
Our results show that the HUMARA clonality assay can improve the histological parameters in differentiating metastatic cancer from second primary cancer.
All other correlations of AR expression in primary tumors and metastases with quantitative (age, prostate cancer volume, number of metastases) or categorical (tumor stage, Gleason score of the primary tumor and metastases) tumor characteristics or with survival were insignificant.
Mutation profiling in mice provides direct evidence that somatic AR variants are selected by therapy, a finding validated in human metastases from distinct treatment groups.
We showed androgen induced epithelial-mesenchymal transition (EMT) in AR-positive bladder cancer cells and promoted tumor metastasis in xenograft models.
Strikingly, 83% of mice with PIN lesions exhibited metastases to draining lymph nodes, marked by relatively differentiated tumor cells expressing markers of basal (p63, cytokeratin 14) and luminal (cytokeratin 8 and androgen receptor) epithelial cells, although none expressed the basal marker, cytokeratin 5.
Lesions affecting tumour suppressor genes usually occur as single events, whereas mutations in genes involved in androgen receptor signalling commonly involve multiple, convergent events in different metastases.
High AR-V9 mRNA expression in CRPC metastases was predictive of primary resistance to abiraterone acetate (HR = 4.0; 95% confidence interval, 1.31-12.2; <i>P</i> = 0.02).<b>Conclusions:</b> AR-V9 may be an important component of therapeutic resistance in CRPC.<i></i>.
Metastases with AR amplification showed high AR and AR-V7 mRNA levels, increased nuclear AR immunostaining, and co-amplification of genes such as YIPF6 in the AR proximity at Xq12.
Moreover, brain dissemination is probably the result of progressive dedifferentiation of primary tumor, shown by reduction of ER and AR expression in metastases.
The concordance of <sup>18</sup>F-FDHT and <sup>18</sup>F-FES uptake on PET with immunohistochemical expression of AR and ER in biopsies of corresponding metastases was analyzed.
Patients and Methods Fifty-six patients with metastatic castration-resistant prostate cancer (mCRPC) with osseous metastases had NaF PET/CT scans performed at baseline and after three cycles of chemotherapy (n = 16) or androgen receptor pathway inhibitors (n = 40).
Accordingly, infiltration of CD3<sup>+</sup> and CD68<sup>+</sup> cells was lower in AR-driven than in non-AR-driven metastases, and tumor cell HLA class I ABC immunoreactivity was inversely correlated with nuclear AR immunoreactivity.