Nuclear androgen receptor staining in bone metastases is related to a poor outcome in prostate cancer patients

Abstract

Androgen receptors (ARs) are probably of importance during all phases of prostate cancer (PC) growth, but their role in bone metastases is largely unexplored. Bone metastases were therefore collected from hormone-naive (nZ11), short-term castrated (nZ7) and castration-resistant PC (CRPC, nZ44) patients by biopsy (nZ4) or at surgery to alleviate symptoms from metastases complications (metastasis surgery, nZ58), and immunostained for nuclear ARs, Ki67, active caspase-3, prostate-specific antigen (PSA) and chromogranin A, and results were related to serum PSA, treatments and outcome. Nuclear AR immunostaining was decreased and apoptosis was increased, but cell proliferation remained largely unaffected in metastases within a few days after surgical castration. In CRPC patients, nuclear AR staining of metastases was increased when compared to short-term castrated patients. The nuclear AR staining score was related to tumour cell proliferation, but it was not associated with other downstream effects of AR activation such as apoptosis and PSA staining, and it was only marginally related to the presence of neuroendocrine tumour cells. Serum PSA at metastasis surgery, although related to outcome, was not associated with AR staining, markers of metastasis growth or PSA staining in metastases. High nuclear AR immunostaining was associated with a particularly poor prognosis after metastasis surgery in CRPC patients, suggesting that such men may benefit from the potent AR blockers now tested in clinical trials.

Mouse models of prostate cancer: picking the best model for the question

“…In human PCa patients, 90% of PCa metastases occur in bone[35], and the majority have strong expression of nuclear AR[158]. In the limited GEM models that develop metastatic bone lesions, the penetrance varies from “rare” up to about 17%.…”

Comparison of different prostatic markers in lymph node and distant metastases of prostate cancer

“…22,23 Since AR overexpression is a late event in the progression of prostate cancer, AR is a potential marker for metastatic prostate cancer. Crnalic et al 22 showed that only two cases out of 58 investigated bone metastases were negative for AR. Concordant with these findings, we also observed a high-expression frequency for AR in distant metastases (91%).…”

Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer

“…Heterogeneity also extends to the distribution and intensity of AR expression, as revealed by immunohistochemical studies of CRPC bone metastases 88, 90–92 . For example, in a study with 44 CRPC bone metastases, 58.1% of patients had moderate (30.4% of cases) to intense (69.6% of cases) AR staining in 76–100% of the tumor cells, whereas 8.8% of the patients in the study had AR staining in just 1–25% of tumor cells 92 . Thus, metastatic CRPC can exist as a mixture of cells displaying a range of AR expression levels.…”