3169

FOXA1

forkhead box A1;FOXA1;forkhead box A1

HNF-3-alpha|HNF-3A|TCF-3A|forkhead box protein A1|hepatocyte nuclear factor 3-alpha|transcription factor 3A

14q21.1

protein-coding

Prognosis of cancers with lymph node metastasis is known to be very poor; however, it is still controversial whether metastatic potential can be evaluated by expression profiles of primary tumors. Therefore, to address this issue, we compared gene expression profiles of 24 esophageal squamous cell carcinomas (ESCCs) with extensive lymph node metastasis and 11 ESCCs with no metastatic lymph node. However, there was no gene cluster distinguishing these two groups, suggesting that lymph node metastasis-associated genes are varied depending on cases or subgroups. Therefore, we applied a recently developed filtering method (S2N') to identify such genes, and successfully extracted 209 genes associated with node status. Among them, over-expression of CALB1, KRT7/CK7, MUC1 and CEA/CEACAM5 in poor prognostic cases with metastatic lymph nodes was confirmed in two sets of ESCCs by RT-PCR. Each often seemed to have glandular cell type-characteristics in both the gene expression and morphology. It was also revealed that FOXA1 siRNA treatment of esophageal cancer cells reduced the mRNA level of both KRT7 and a stabilizer of epithelial-mesenchymal transition (EMT) regulator LOXL2, and that both FOXA1 and LOXL2 siRNAs reduced invasion and migration of ESCC cells. In 15 KRT7-expressing ESCCs with metastatic lymph nodes, 60% expressed FOXA1 and 33% expressed both FOXA1 and LOXL2. These results suggest that FOXA1 induces not only KRT7 but also LOXL2 in a subset of poor prognostic ESCCs with metastatic lymph nodes, and it is also plausible, that other FOXA1 downstream genes could be therapeutic targets of poor prognostic ESCCs.

Dysregulation of the developmental gene anterior gradient protein 2 (AGR2) has been associated with a metastatic phenotype, but its mechanism of action and control in prostate cancers is unknown. In this study, we show that overexpression of AGR2 promotes the motility and invasiveness of nonmetastatic LNCaP tumor cells, whereas silencing of AGR2 in the metastatic derivative C4-2B blocks invasive behavior. ErbB3 binding protein 1 (EBP1), a putative repressor of AGR2, is attenuated in prostate cancer. We show that the anti-invasive effect of EBP1 occurs, at least in part, through its ability to inhibit AGR2 expression. Mechanistic investigations indicate that EBP1 downregulates Foxa1- and Foxa2-stimulated AGR2 transcription and decreases metastatic behavior. In contrast, EBP1 ablation upregulates AGR2 via Foxa1- and Foxa2-stimulated AGR2 promoter activity and increases metastatic behavior. In both prostate cell lines and primary tumors, we documented an inverse correlation between EBP1 and AGR2 levels. Collectively, our results reveal an EBP1-Foxa-AGR2 signaling circuit with functional significance in metastatic prostate cancer.

AIMS: expression of forkhead-box protein A1 (FOXA1), a transcription factor important for normal development of the prostate gland, is thought to be controlled by steroid hormones and GATA3. The aim of this study was to investigate the expression and potential role of FOXA1 and GATA3 transcription factors as prognostic factors in prostate cancer. METHODS AND RESULTS: expression of FOXA1, GATA3 and androgen receptor (AR) was retrospectively analysed by immunohistochemistry in a series of 80 primary tumours and 28 metastatic prostate cancers, including 15 matched paired samples. Nuclear AR expression did not significantly differ between primary and metastatic tumours. High-level nuclear FOXA1 expression was seen in 19% of primary and 89% of metastatic tumours (P < 0.0001). FOXA1 expression correlated positively with tumour size, extraprostatic extension, angiolymphatic invasion, AR and lymph node metastases at diagnosis, but did not correlate with age, T stage, Gleason score, presence of prostatic intraepithelial neoplasia or multifocality, seminal vesicle or perineural invasion, or surgical excision margin status. expression of GATA3 was not seen in either normal epithelium or tumour. CONCLUSIONS: Our preliminary analyses suggest that high-level FOXA1 expression is associated with the development of metastatic prostate cancer. If these data are confirmed, FOXA1 expression could be used to classify patients at higher risk for metastases.