Dataset Information

Switch in FOXA1 status associates with endometrial cancer progression.

ABSTRACT:

Background

The transcription factor Forkhead box A1 (FOXA1) is suggested to be important in hormone dependent cancers, although with little data for endometrial cancer. We investigated expression levels of FOXA1 in primary and metastatic endometrial cancer in relation to clinical phenotype, and transcriptional alterations related to FOXA1 status.

Methods

Protein expression of FOXA1 was explored by immunohistochemistry in 529 primary and 199 metastatic endometrial carcinoma lesions. mRNA levels from corresponding 158 fresh frozen primary and 42 metastatic lesions were analyzed using Agilent Microarrays (44k) in parallel.

Results

Low FOXA1 protein expression in primary tumors significantly correlated with low FOXA1 mRNA, high age, non-endometrioid histology, high grade, loss of ERα and PR and poor survival (all p-values <0.05). Through a Connectivity Map search, HDAC inhibitors were suggested as potential treatment for patients with low FOXA1 expression. An increase in FOXA1 expression was observed from primary to metastatic lesions and it correlated with CDKN2A expression in metastases.

Conclusion

Low FOXA1 is associated with poor survival and suggests a potential for HDAC inhibitors in endometrial carcinoma. A switch in FOXA1 expression from primary to metastatic lesions is observed and gene expression indicates a link between FOXA1 and CDKN2A in metastatic lesions.

SUBMITTER: Tangen IL

PROVIDER: S-EPMC4029819 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Switch in FOXA1 status associates with endometrial cancer progression.

Tangen Ingvild Løberg IL Krakstad Camilla C Halle Mari K MK Werner Henrica M J HM Oyan Anne M AM Kusonmano Kanthida K Petersen Kjell K Kalland Karl Henning KH Akslen Lars A LA Trovik Jone J Hurtado Antoni A Salvesen Helga B HB

PloS one 20140521 5

<h4>Background</h4>The transcription factor Forkhead box A1 (FOXA1) is suggested to be important in hormone dependent cancers, although with little data for endometrial cancer. We investigated expression levels of FOXA1 in primary and metastatic endometrial cancer in relation to clinical phenotype, and transcriptional alterations related to FOXA1 status.<h4>Methods</h4>Protein expression of FOXA1 was explored by immunohistochemistry in 529 primary and 199 metastatic endometrial carcinoma lesions ...[more]

PMID: 24849812

Similar Datasets

Project description:BackgroundIncreasing evidence suggests that forkhead box A1 (FOXA1) is frequently dysregulated in many types of human cancers. However, the exact function and mechanism of FOXA1 in human endometrial cancer (EC) remains unclear.MethodsFOXA1 expression, androgen receptor (AR) expression, and the relationships of these two markers with clinicopathological factors were determined by immunohistochemistry analysis. FOXA1 and AR were up-regulated by transient transfection with plasmids, and were down-regulated by transfection with siRNA or short hairpin RNA (shRNA). The effects of FOXA1 depletion and FOXA1 overexpression on AR-mediated transcription as well as Notch pathway and their impact on EC cell proliferation were examined by qRT-PCR, western blotting, co-immunoprecipitation, ChIP-PCR, MTT, colony-formation, and xenograft tumor-formation assays.ResultsWe found that the expression of FOXA1 and AR in ECs was significantly higher than that in a typical hyperplasia and normal tissues. FOXA1 expression was significantly correlated with AR expression in clinical tissues. High FOXA1 levels positively correlated with pathological grade and depth of myometrial invasion in EC. High AR levels also positively correlated with pathological grade in EC. Moreover, the expression of XBP1, MYC, ZBTB16, and UHRF1, which are downstream targets of AR, was promoted by FOXA1 up-regulation or inhibited by FOXA1 down-regulation. Co-immunoprecipitation showed that FOXA1 interacted with AR in EC cells. ChIP-PCR assays showed that FOXA1 and AR could directly bind to the promoter and enhancer regions upstream of MYC. Mechanistic investigation revealed that over-expression of Notch1 and Hes1 proteins by FOXA1 could be reversed by AR depletion. In addition, we showed that down-regulation of AR attenuated FOXA1-up-regulated cell proliferation. However, AR didn't influence the promotion effect of FOXA1 on cell migration and invasion. In vivo xenograft model, FOXA1 knockdown reduced the rate of tumor growth.ConclusionsThese results suggest that FOXA1 promotes cell proliferation by AR and activates Notch pathway. It indicated that FOXA1 and AR may serve as potential gene therapy in EC.

Dataset Information

Switch in FOXA1 status associates with endometrial cancer progression.

Background

Methods

Results

Conclusion

Publications

Switch in FOXA1 status associates with endometrial cancer progression.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets