Hepatic adenomas: analysis of sex steroid receptor status and the Wnt signaling pathway.
Hepatic adenomas are strongly linked to excess hormonal exposure, but little else is known about their pathogenesis. The Wnt signaling pathway, which is activated in both hepatocellular carcinomas and hepatoblastomas, has not been studied in hepatic adenomas. Fifteen hepatic adenomas were studied by immunohistochemistry for estrogen, progesterone, and androgen receptors (ER, PR, AR, respectively) and correlated with the results of immunostaining for beta-catenin. Direct sequencing was performed to look for mutations in key genes involved in the Wnt signaling pathway: Exon 3 of beta-catenin encompassing the glycogen synthase kinase 3beta (GSK-3beta) phosphorylation region and the mutational cluster region of the adenomatosis polyposis coli protein (APC). Analysis for loss of heterozygosity (LOH) at chromosome 5q was also performed. Immunostaining for both ER and PR was present in 11/15 (73%) adenomas, and staining with one hormone receptor was positively associated with staining for the other receptor. AR positivity was present in 3/15 cases. Nuclear accumulation of beta-catenin was present in 7/15 (46%) of adenomas, indicating activation of the Wnt signaling pathway. However, no beta-catenin mutations, no APC mutations in the mutational cluster region, and no 5q LOH were detected. Two APC polymorphisms of unknown significance were seen. No clear association between beta-catenin nuclear accumulation and hormone receptor positivity was discerned. Activation of the Wnt signaling pathway appears to be important in a subset of hepatic adenomas but does not result from common beta-catenin or APC mutations and does not appear to be directly linked to hormonal receptor status.
Torbenson
Michael
M
Division of Gastrointestinal/Liver Pathology, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2196, USA. mtorben@pds.path.jhu.edu
Lee
Jae-Hyuk
JH
Choti
Michael
M
Gage
Wesley
W
Abraham
Susan C
SC
Montgomery
Elizabeth
E
Boitnott
John
J
Wu
Tsung-Teh
TT
D018248:Adenoma, Liver Cell / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D002895:Chromosomes, Human, Pair 5; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000737:chemistry; D005260:Female; D017491:Genes, APC; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D019656:Loss of Heterozygosity; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D011987:Receptors, Steroid / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D017931:DNA Primers; D011518:Proto-Oncogene Proteins; D011987:Receptors, Steroid; D015534:Trans-Activators; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin