Is PTEN loss associated with clinical outcome measures in human prostate cancer?

Abstract

Inactivating PTEN mutations are commonly found in prostate cancer, resulting in an increased activation of Akt. In this study, we investigate the role of PTEN deletion and protein expression in the development of hormone-refractory prostate cancer using matched hormone-sensitive and hormone-refractory tumours. Fluorescent in situ hybridisation and immunohistochemistry was carried out to investigate PTEN gene deletion and PTEN protein expression in the transition from hormone-sensitive to hormone-refractory prostate cancer utilising 68 matched hormone sensitive and hormone-refractory tumour pairs (one before and one after hormone relapse). Heterogeneous PTEN gene deletion was observed in 23% of hormone sensitive tumours. This increased significantly to 52% in hormone-refractory tumours (P=0.044). PTEN protein expression was observed in the membrane, cytoplasm and the nucleus. In hormone sensitive tumours, low levels of cytoplasmic PTEN was independently associated with shorter time to relapse compared to high levels of PTEN (P=0.028, hazard ratio 0.51 (95%CI 0.27-0.93). Loss of PTEN expression in the nucleus of hormone sensitive tumours was independently associated with disease-specific survival (P=0.031, hazard ratio 0.52, 95%CI 0.29-0.95). The results from this study demonstrate a role for both cytoplasmic and nuclear PTEN in progression of prostate cancer to the hormone-refractory state.

Figure 1

(A) shows an example of fluorescent in situ hybridisation for chromosome 10 (red signal) and PTEN (green signal). (B) Shows an example of immunohistochemistry for PTEN protein expression; in hormone-sensitive prostate cancer, both cytoplasmic expression and nuclear expression are present. (C) Western blot analysis for PTEN protein to confirm antibody specificity. LNCaP cells do not express PTEN protein, whereas DU145 cells do express PTEN protein. Lane 1, hormone-sensitive LNCaP cell lysates; lane 2, hormone-refractory LNCaP cell lysates; lane 3, DU145 cell lysates.

Figure 2

(A) Shows a Kaplan–Meier plot for high (above the median, solid line) and low (below the median, dotted line) PTEN cytoplasmic expression and time to biochemical relapse (P=0.027). (B) Shows a Kaplan–Meier plot for high (above the median, solid line) and low (below the median, dotted line) PTEN cytoplasmic expression for patients that took longer than 30 months to relapse (P=0.0035). (C) shows a Kaplan–Meier plot for high (above the median, solid line) and low (below the median, dotted line) PTEN cytoplasmic expression and disease-specific survival (labelled overall survival; P=0.072). (D) Shows a Kaplan–Meier plot for patients with tumours that have membrane PTEN expression (solid line) compared to patients whose tumours do not have nuclear PTEN expression (dotted line) and disease-specific survival (labelled overall survival; P=0.002). (E) Shows a Kaplan–Meier plot for patients with tumours that have nuclear PTEN expression (dotted line) compared to patients whose tumours do not have nuclear PTEN expression (solid line) and time to biochemical relapse (P=0.078). (F) Shows a Kaplan–Meier plot for patients with tumours that have nuclear PTEN expression (solid line) compared to patients whose tumours do not have nuclear PTEN expression (dotted line) and disease-specific survival (labelled overall survival; P=0.003).