Predictive value of PTEN and AR coexpression of sustained responsiveness to hormonal therapy in prostate cancer--a pilot study.

One limitation of current biochemical or histologic analysis of advanced prostate cancer (PC; T(3)/T(4) +/- N(x) M(x)) is the ability to identify on first diagnostic biopsy patients who will make a durable response to hormone ablation therapy. The aim of this study was to assess the predictive value (sustained response to hormonal therapy and clinical outcome (relapse-free and overall survival)) of phosphatase and tensin homolog (PTEN) and the androgen receptor (AR) immunoexpression in the presenting biopsy. Analysis was performed on 47 samples (10 cases of benign prostatic hyperplasia and 37 hormone-naive PCs). Patients selected represented two stages in the natural history of PC: The "clinical metastatic androgen-responsive" (androgen-dependent PC, ADPC) and the "clinical metastatic androgen-resistant" (androgen-independent PC, AIPC). Reduced immunoreactivity (IR) of either or both PTEN/AR in the initial hormone-naive PC samples was observed with increased frequency in AIPCs. In the ADPC group, low PTEN and/or AR-IR was associated with a shorter median relapse-free survival, i.e., at 30 months after surgery, the probability of relapse-free survival for high expressors of PTEN and AR was 85.7% (SEM = 9.3) compared with only 16.6% (SEM = 15.2) in low expressors. At 36 months, only 28.5% (SEM = 9.3) of ADPC high expressors had experienced a biochemical relapse compared with 100% of low expressors (hazard ratio, 4.6; 95% confidence interval, 4.7-146.8). Further studies analyzing the coexpression of PTEN and AR should be undertaken to validate this pilot study and the utility of these biomarkers in routine histopathologic workup of patients with PC.

Phosphorylation of both EGFR and ErbB2 is a reliable predictor of prostate cancer cell proliferation in response to EGF.

Despite multiple reports of overexpression in prostate cancer (PC), the reliance of PC cells on activated epidermal growth factor receptor (EGFR) and its downstream signaling to phosphoinositide 3'-kinase/Akt (PI3K/Akt/PTEN) and/or mitogen-activated protein kinase (MAPK/ERK) pathways has not been fully elucidated. In this study, we compared the role of EGF-mediated signaling in nonmalignant (BPH-1, PNT1A, and PNT1B) and PC cell lines (DU145, PC3, LNCaP, and CWR22Rv1). EGF-induced proliferation was observed in all EGFR-expressing PC cells except PC3, indicating that EGFR expression does not unequivocally trigger proliferation following EGF stimulation. ErbB2 recruitment potentiated EGF-induced signals and was associated with the most pronounced effects of EGF despite low EGFR expression. In this way, the sum of EGFR and ErbB2 receptor phosphorylation proved to be a more sensitive indicator of EGF-induced proliferation than quantification of the expression of either receptor alone. Both Akt and ERK were rapidly phosphorylated in response to EGF, with ERK phosphorylation being the weakest in PC3 cells. Extrapolation of these findings to clinical PC suggests that assessment of phosphorylated EGFR + ErbB2 together could serve as a marker for sensitivity to anti-EGFR-targeted therapies.

Topographical expression of class IA and class II phosphoinositide 3-kinase enzymes in normal human tissues is consistent with a role in differentiation.

BACKGROUND: Growth factor, cytokine and chemokine-induced activation of PI3K enzymes constitutes the start of a complex signalling cascade, which ultimately mediates cellular activities such as proliferation, differentiation, chemotaxis, survival, trafficking, and glucose homeostasis. The PI3K enzyme family is divided into 3 classes; class I (subdivided into IA and IB), class II (PI3K-C2alpha, PI3K-C2beta and PI3K-C2gamma) and class III PI3K. Expression of these enzymes in human tissue has not been clearly defined. METHODS: In this study, we analysed the immunohistochemical topographical expression profile of class IA (anti-p85 adaptor) and class II PI3K (PI3K-C2alpha and PI3K-C2beta) enzymes in 104 formalin-fixed, paraffin embedded normal adult human (age 33-71 years, median 44 years) tissue specimens including those from the gastrointestinal, genitourinary, hepatobiliary, endocrine, integument and lymphoid systems. Antibody specificity was verified by Western blotting of cell lysates and peptide blocking studies. Immunohistochemistry intensity was scored from undetectable to strong. RESULTS: PI3K enzymes were expressed in selected cell populations of epithelial or mesenchymal origin. Columnar epithelium and transitional epithelia were reactive but mucous secreting and stratified squamous epithelia were not. Mesenchymal elements (smooth muscle and endothelial cells) and glomerular epithelium were only expressed PI3K-C2alpha while ganglion cells expressed p85 and PI3K-C2beta. All three enzymes were detected in macrophages, which served as an internal positive control. None of the three PI3K isozymes was detected in the stem cell/progenitor compartments or in B lymphocyte aggregates. CONCLUSIONS: Taken together, these data suggest that PI3K enzyme distribution is not ubiquitous but expressed selectively in fully differentiated, non-proliferating cells. Identification of the normal in vivo expression pattern of class IA and class II PI3K paves the way for further analyses which will clarify the role played by these enzymes in inflammatory, neoplastic and other human disease conditions.

Androgen-independent prostate cancer: potential role of androgen and ErbB receptor signal transduction crosstalk.

In prostate cancer (PC), increasing evidence suggests that androgen receptor (AR) signalling is functional under conditions of maximal androgen blockade. PC cells survive and proliferate in the altered hormonal environment possibly by interactions between growth factor-activated pathways and AR signalling. The present review article summarizes the current evidence of this crosstalk and focuses on the interactions among the ErbB receptor network, its downstream pathways, and the AR. The potential role of this crosstalk in the development of androgen independence and in relation to antiandrogen therapy is discussed. Such interactions provide insight into possible complementary or additional strategies in the management of PC.