RGD Reference Report - Mapping a sex hormone-sensitive gene determining female resistance to liver carcinogenesis in a congenic F344.BN-Hcs4 rat. - Rat Genome Database

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Mapping a sex hormone-sensitive gene determining female resistance to liver carcinogenesis in a congenic F344.BN-Hcs4 rat.

Authors: De Miglio, MR  Virdis, P  Calvisi, DF  Frau, M  Muroni, MR  Simile, MM  Daino, L  Careddu, GM  Sanna-Passino, E  Pascale, RM  Feo, F 
Citation: De Miglio MR, etal., Cancer Res. 2006 Nov 1;66(21):10384-90.
RGD ID: 1599590
Pubmed: PMID:17079458   (View Abstract at PubMed)
DOI: DOI:10.1158/0008-5472.CAN-06-2881   (Journal Full-text)

Hepatocellular carcinoma (HCC) is prevalent in human and rodent males. Hepatocarcinogenesis is controlled by various genes in susceptible F344 and resistant Brown Norway (BN) rats. B alleles at Hcs4 locus, on RNO16, control neoplastic nodule volume. We constructed the F344.BN-Hcs4 recombinant congenic strain (RCS) by introgressing a 4.41-cM portion of Hcs4 from BN strain in an isogenic F344 background. Preneoplastic and neoplastic lesions were induced by the "resistant hepatocyte" protocol. Eight weeks after initiation, lesion volume and positivity for proliferating cell nuclear antigen (PCNA) were much higher in lesions of F344 than BN rats of both sexes. These variables were lower in females than in males. Lesion volume and PCNA values of male RCS were similar to those of F344 rats, but in females corresponded to those of BN females. Carcinomatous nodules and HCC developed at 32 and 60 weeks, respectively, in male F344 and congenics and, rarely, in F344 females. BN and congenic females developed only eosinophilic/clear cells nodules. Gonadectomy of congenic males, followed by beta-estradiol administration, caused a decrease in Ar expression, an increase in Er-alpha expression, and development of preneoplastic lesions comparable to those from BN females. Administration of testosterone to gonadectomized females led to Ar increase and development of preneoplastic lesions as in F344 males. This indicates a role of homozygous B alleles at Hcs4 in the determination of phenotypic patterns of female RCS and presence at Hcs4 locus of a high penetrance gene(s), activated by estrogens and inhibited/unaffected by testosterone, conferring resistance to females in which the B alleles provide higher resistance.

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Mammalian Phenotype

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Hcas8Ratincreased hepatocyte proliferation  IDA  RGD 
Hcas8Ratincreased hepatoma incidence  IDA  RGD 
BN/CrliRatincreased liver tumor incidence inducedIAGPN-nitrosodiethylaminecompared to F344/Crli RGD 

Objects Annotated

Hcas8  (Hepatocarcinoma susceptibility QTL 8)

Additional Information