Predominant modifier of extreme liver cancer susceptibility in C57BR/cdJ female mice localized to 6 Mb on chromosome 17

McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, 1400 University Avenue, Madison, WI 53706, USA.
Carcinogenesis (Impact Factor: 5.33). 04/2009; 30(5):879-85. DOI: 10.1093/carcin/bgp054
Source: PubMed


Sex hormones influence the susceptibility of inbred mice to liver cancer. C57BR/cdJ (BR) females are extremely susceptible
to spontaneous and chemically induced liver tumors, in part due to a lack of protection against hepatocarcinogenesis normally
offered by ovarian hormones. BR males are also moderately susceptible, and the susceptibility of both sexes of BR mice to
liver tumors induced with N,N-diethylnitrosamine relative to the resistant C57BL/6J (B6) strain is caused by two loci designated Hcf1 and Hcf2 (hepatocarcinogenesis in females) located on chromosomes 17 and 1, respectively. The Hcf1 locus on chromosome 17 is the predominant modifier of liver cancer in BR mice. To validate the existence of this locus and
investigate its potential interaction with Hcf2, congenic mice for each region were generated. Homozygosity for the B6.BR(D17Mit164-D17Mit2) region resulted in a 4-fold increase in liver tumor multiplicity in females and a 4.5-fold increase in males compared with
B6 controls. A series of 16 recombinants covering the entire congenic region was developed to further narrow the area containing
Hcf1. Susceptible heterozygous recombinants demonstrated a 3- to 7-fold effect in females and a 1.5- to 2-fold effect in males
compared with B6 siblings. The effect in susceptible lines completely recapitulated the susceptibility of heterozygous full-length
chromosome 17 congenics and furthermore narrowed the location of the Hcf1 locus to a single region of the chromosome from 30.05 to 35.83 Mb.

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Available from: Norman Drinkwater
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    • "Inbred strains of mice differ greatly in their susceptibilities to spontaneous liver tumors (Drinkwater, 1988). This inter-strain variation of wild-type mice represents a valuable resource and is still used to identify liver tumor susceptibility genes (Peychal et al., 2009). Early on, efforts were made to develop better models, where tumors would develop more rapidly, with high penetrance and synchronous kinetics. "
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    ABSTRACT: Hepatocellular carcinoma (HCC), the most common form of primary liver cancer is the third leading cause of cancer-related cell death in human and the fifth in women worldwide. The incidence of HCC is increasing despite progress in identifying risk factors, understanding disease etiology and developing anti-viral strategies. Therapeutic options are limited and survival after diagnosis is poor. Therefore, better preventive, diagnostic and therapeutic tools are urgently needed, in particular given the increased contribution from systemic metabolic disease to HCC incidence worldwide. In the last three decades, technological advances have facilitated the generation of genetically engineered mouse models (GEMMs) to mimic the alterations frequently observed in human cancers or to conduct intervention studies and assess the relevance of candidate gene networks in tumor establishment, progression and maintenance. Because these studies allow molecular and cellular manipulations impossible to perform in patients, GEMMs have improved our understanding of this complex disease and represent a source of great potential for mechanism-based therapy development. In this review, we provide an overview of the current state of HCC modeling in the mouse, highlighting successes, current challenges and future opportunities.
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    • "predominant locus responsible for this difference to a 6 Mb region on Chromosome 17 (Peychal et al., 2009). This region corresponds to part of the chromosome 6p region amplified in the majority of late-stage HCC (Santos et al., 2007; Chochi et al., 2009). "

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    ABSTRACT: Mice treated neonatally with diethylnitrosamine (DEN) develop liver tumors in a male-dominant manner, reflecting the male bias in human hepatocellular carcinoma. Evidence suggests that estrogen, androgen, prolactin (PRL) and growth hormone (GH) modify liver tumorigenesis. We determined the roles of estrogen receptor-α (ERα) and prolactin receptor (PRLR) using receptor null mice, ERαKO (C57Bl/6J) and PRLR-KO (129Ola-X-C57BL/6), in the neonatal-DEN model of liver tumorigenesis. In both mouse strains, females had reduced tumorigenesis compared with males (P < 0.01), regardless of ERα or PRLR status. Tumorigenesis was not affected by ovariectomy in C57Bl/6J mice but it was increased by ovariectomy in the mixed strain, 129Ola-X-C57BL/6, regardless of PRLR status. ERαKO males had 47% fewer tumors than ERα wild-type males (P < 0.01). On the other hand, estradiol treatment protected against tumorigenesis in males only in the presence of ERα. As evidenced by liver gene expression, lack of ERα did not alter the pattern of GH secretion in males but resulted in the male GH pattern in females. These observations indicate that ERα is not required for lower tumorigenesis in females, but it is required for the protective effects of exogenously delivered estradiol. Unexpectedly, the results indicate that ERα plays a role in promotion of liver tumors in males. In addition, it can be concluded that sex differences in liver tumorigenesis cannot be explained by the sexually dimorphic pattern of GH secretion. The results also rule out PRL as the mediator of the protective effect of the ovaries.
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