Genetic determinants modulate susceptibility to pregnancy-associated tumourigenesis in a recombinant line of Min mice.
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.
Suraweera
N
N
ICMS, Barts and The London Queen Mary's School of Medicine and Dentistry, and Cancer Research UK Colorectal Cancer Unit and Academic Department of Pathology, St Mark's Hospital, Harrow, Middx, UK.
Haines
J
J
McCart
A
A
Rogers
P
P
Latchford
A
A
Coster
M
M
Polanco-Echeverry
G
G
Guenther
T
T
Wang
J
J
Sieber
O
O
Tomlinson
I
I
Silver
A
A
D011125:Adenomatous Polyposis Coli / Q000235:genetics*; D000818:Animals; D002874:Chromosome Mapping; D004195:Disease Models, Animal; D005260:Female; D005787:Gene Frequency; D017491:Genes, APC; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic / Q000235:genetics*; D011960:Receptors, Estrogen / Q000235:genetics
D005819:Genetic Markers; D011960:Receptors, Estrogen