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Mapping a sex hormone–sensitive gene determining female resistance to liver carcinogenesis in a congenic f344.bn-hcs4 rat

De Miglio, Maria Rosaria and Virdis, Patrizia and Calvisi, Diego Francesco and Frau, Maddalena and Muroni, Maria Rosaria and Simile, Maria Maddalena and Daino, Lucia and Careddu, Giovanni Mario and Sanna Passino, Eraldo and Pascale, Rosa Maria and Feo, Francesco (2006) Mapping a sex hormone–sensitive gene determining female resistance to liver carcinogenesis in a congenic f344.bn-hcs4 rat. Cancer Research, Vol. 66 (21), p. 10384-10390. eISSN 0008-5472. Article.

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DOI: 10.1158/0008-5472.CAN-06-2881

Abstract

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 β-estradiol administration, caused a decrease in Ar expression, an increase in Er-α 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.

Item Type:Article
ID Code:4320
Status:Published
Refereed:Yes
Uncontrolled Keywords:Cell nucleus antigen, estradiol, sex hormone
Subjects:Area 07 - Scienze agrarie e veterinarie > VET/09 Clinica chirurgica veterinaria
Area 06 - Scienze mediche > MED/04 Patologia generale
Divisions:001 Università di Sassari > 01 Dipartimenti > Patologia e clinica veterinaria
001 Università di Sassari > 01 Dipartimenti > Scienze biomediche
Publisher:American Association for Cancer Research
eISSN:0008-5472
Deposited On:20 Aug 2010 13:31

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