Genetic determinants modulate susceptibility to pregnancy-associated tumourigenesis in a recombinant line of Min mice.

Journal article

Min mice provide a good model of human familial adenomatous polyposis. Recently, we have reported on two recombinant inbred lines (I and V) and the location of a modifier (Mom3) close to Apc, which altered polyp numbers in our mice possibly by modifying the frequency of wild-type (WT) allele loss at Apc; mice with severe disease (line V) showed elevated rates of loss. We now show that in line I only, a single pregnancy caused a significant increase in adenoma multiplicity compared with virgin controls (P<0.001) and that an additional pregnancy conferred a similar risk. Pregnancy was linked to both adenoma initiation and enhanced tumour growth in line I mice, and interline crosses indicated that susceptibility to pregnancy-associated adenomas was under genetic control. We found no evidence for the involvement of oestrodial metabolizing genes or the oestrogen receptors (Esr1 and 2) in tumour multiplicity. Importantly, a significantly elevated frequency of WT allele loss at Apc was observed in adenomas from parous mice (line and backcrossed) carrying the line I Min allele relative to equivalent virgin controls (P=0.015). Our results provide the first experimental evidence for genetic determinants controlling pregnancy-associated tumourigenesis; analogous genetic factors may exist in humans.

Authors: Suraweera, N; Haines, J; McCart, A; Rogers, P; Latchford, A

• Publication status: Published
• Journal: Human molecular genetics
• Volume: 15
• Issue: 23
• Pages: 3429-3435
• Publication date: 2006-12-01
• DOI: 10.1093/hmg/ddl419
• EISSN: 1460-2083
• ISSN: 0964-6906
• Language: English
• Keywords: Pregnancy; Humans; Genetic Markers; Mice, Mutant Strains; Animals; Pregnancy Complications, Neoplastic; Adenomatous Polyposis Coli; Mice; Female; Chromosome Mapping; Gene Frequency; Genes, APC; Genetic Predisposition to Disease; Receptors, Estrogen; Disease Models, Animal