Depletion of hepatocyte nuclear estrogen receptor expression is associated with promotion of tamoxifen induced GST-P foci to tumours in rat liver.
The expression of hepatocyte nuclear estrogen receptor (ER) in putative preneoplastic foci, adenomas and carcinomas, induced by the rat liver carcinogen tamoxifen, has been examined immunohistologically. ER staining of normal rat liver shows between 30-50% of hepatocyte nuclei to be positive, depending on fixation. Depletion of ER was defined as <10% of cells in foci or tumours staining for nuclear ER. A proportion of all but the smallest glutathione-S-transferase, placental form (GST-P) expressing foci had depleted expression of nuclear ER. The percentage of GST-P expressing foci with depletion of nuclear ER increased with the size of the foci. The liver adenomas and carcinomas induced by tamoxifen showed a high incidence (90%) of depletion of ER. This suggests that abnormal expression of the ER is associated with the promotion of putative preneoplastic foci to adenomas and carcinomas in tamoxifen exposed rat livers. Dysfunction of the ER could contribute to selective continued stimulation of initiated cells that would be consistent with a role for modification of the ER in target cells and the promotion stage of liver cancer. Liver tumours induced by other carcinogens in both sexes of rat were also found to have a high incidence of ER depletion, indicating that this could be a general regulatory mechanism for rat liver tumour promotion, irrespective of the possible estrogen like action of individual carcinogens.
Carthew
P
P
MRC Toxicology Unit, University of Leicester, UK.
Edwards
R E
RE
Nolan
B M
BM
D000236:Adenoma / Q000378:metabolism*; D000348:Aflatoxins / Q000494:pharmacology; D000818:Animals; D002277:Carcinoma / Q000378:metabolism*; D002451:Cell Compartmentation / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism*; D004128:Dimethylnitrosamine / Q000494:pharmacology; D005260:Female; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008113:Liver Neoplasms / Q000139:chemically induced*; D008297:Male; D011230:Precancerous Conditions / Q000139:chemically induced / Q000201:enzymology; D051381:Rats; D011916:Rats, Inbred F344; D011960:Receptors, Estrogen / Q000378:metabolism*; D013629:Tamoxifen / Q000494:pharmacology*; D013853:Thioacetamide / Q000494:pharmacology
D000348:Aflatoxins; D007527:Isoenzymes; D011960:Receptors, Estrogen; D013853:Thioacetamide; D013629:Tamoxifen; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; C496558:Gstp1 protein, rat; D004128:Dimethylnitrosamine