Epithelial-mesenchymal transition (EMT) is important for tumour cell invasion and
metastasis and is a feature of aggressive
carcinomas. EMT is characterised by reduced
E-cadherin and increased
N-cadherin expression (EN-switch), and increased expression of the EMT-regulating
transcription factor Forkhead box
protein C2 (FOXC2) has been associated with progression and poor prognosis in various
malignancies. FOXC2 was recently highlighted as a novel
therapy target in
prostate cancer, but survival data on FOXC2 are lacking. This study evaluates the expression of FOXC2,
E-cadherin and
N-cadherin in different prostatic tissues focusing on EMT, clinico-pathological phenotype, recurrence and patient survival. Tissue microarray sections from 338 radical
prostatectomies (1986-2007) with long and complete follow-up, 33
castration resistant
prostate cancers, 33 non-skeletal
metastases, 13 skeletal
metastases and 41 prostatic
hyperplasias were stained immunohistochemically for FOXC2,
E-cadherin and
N-cadherin. FOXC2 was strongly expressed in primary
carcinomas, including
castration resistant tumours and metastatic lesions as compared to
benign prostatic hyperplasia. A hybrid epithelial-mesenchymal phenotype, with co-expression of
E-cadherin and
N-cadherin, was found in the majority of skeletal
metastases and in a substantial proportion of
castration resistant tumours. In localised
carcinomas, the EN-switch was associated with adverse clinico-pathological variables, such as extra-prostatic extension, high pathological stage and lymph node infiltration. In univariate survival analyses of the clinically important, large subgroup of 199 patients with Gleason score 7, high FOXC2 expression and EN-switching were significantly associated with shorter time to clinical recurrence, skeletal
metastases and
cancer specific death. In multivariate Cox' survival analysis, high FOXC2 and the EN-switch, together with Gleason grade group (GG3 versus GG2), were independent predictors of time to these end-points. High FOXC2 gene expression (
mRNA) was also related to patient outcome, validating our immunohistochemical findings. FOXC2 and factors signifying EMT or its intermediate states may prove important as
biomarkers for aggressive disease and are potential novel
therapy targets in
prostate cancer.