Switch in FOXA1 status associates with endometrial cancer progression.
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.


CONCLUSIONS
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.
Center for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway.
Ingvild Løberg
IL
Tangen
Center for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway.
Camilla
C
Krakstad
Center for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway.
Mari K
MK
Halle
Center for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway.
Henrica M J
HM
Werner
Center for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Microbiology, Haukeland University Hospital, Bergen, Norway.
Anne M
AM
Oyan
Center for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway; Computational Biology Unit, University of Bergen, Bergen, Norway.
Kanthida
K
Kusonmano
Computational Biology Unit, University of Bergen, Bergen, Norway.
Kjell
K
Petersen
Center for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Microbiology, Haukeland University Hospital, Bergen, Norway.
Karl Henning
KH
Kalland
Center for Cancer Biomarkers, Department of Clinical Medicine, University of Bergen, Bergen, Norway; Department of Pathology, Haukeland University Hospital, Bergen, Norway.
Lars A
LA
Akslen
Center for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway.
Jone
J
Trovik
Breast Cancer Research group, Centre for Molecular Medicine Norway, University of Oslo, Oslo, Norway.
Antoni
A
Hurtado
Center for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway.
Helga B
HB
Salvesen
D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D018450:Disease Progression; D016889:Endometrial Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D009362:Neoplasm Metastasis; D010641:Phenotype; D011379:Prognosis; D014158:Transcription, Genetic / Q000187:drug effects
D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; D047628:Estrogen Receptor alpha; D051541:Hepatocyte Nuclear Factor 3-alpha; D056572:Histone Deacetylase Inhibitors