Interaction between genetic susceptibility and early-life environmental exposure determines tumor-suppressor-gene penetrance.
Gene-environment interactions are important determinants of cancer risk. Traditionally, gene-environment interactions are thought to contribute to tumor-suppressor-gene penetrance by facilitating or inhibiting the acquisition of additional somatic mutations required for tumorigenesis. Here, we demonstrate that a distinctive type of gene-environment interaction can occur during development to enhance the penetrance of a tumor-suppressor-gene defect in the adult. Using rats carrying a germ-line defect in the tuberous sclerosis complex 2 (Tsc-2) tumor-suppressor gene predisposed to uterine leiomyomas, we show that an early-life exposure to diethylstilbestrol during development of the uterus increased tumor-suppressor-gene penetrance from 65% to >90% and tumor multiplicity and size in genetically predisposed animals, but it failed to induce tumors in wild-type rats. This exposure was shown to impart a hormonal imprint on the developing uterine myometrium, causing an increase in expression of estrogen-responsive genes before the onset of tumors. Loss of function of the normal Tsc-2 allele remained the rate-limiting event for tumorigenesis; however, tumors that developed in exposed animals displayed an enhanced proliferative response to steroid hormones relative to tumors that developed in unexposed animals. These data suggest that exposure to environmental factors during development can permanently reprogram normal physiological tissue responses and thus lead to increased tumor-suppressor-gene penetrance in genetically susceptible individuals.
Cook
Jennifer D
JD
Graduate School of Biomedical Sciences, University of Texas, 6655 Travis Street, Suite 300, Houston, TX 77030, USA.
Davis
Barbara J
BJ
Cai
Sheng-Li
SL
Barrett
J Carl
JC
Conti
Claudio J
CJ
Walker
Cheryl Lyn
CL
D000818:Animals; D015153:Blotting, Western; D004054:Diethylstilbestrol / Q000633:toxicity*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D012739:Gonadal Steroid Hormones / Q000378:metabolism; D007150:Immunohistochemistry; D007889:Leiomyoma / Q000235:genetics* / Q000378:metabolism; D009215:Myometrium / Q000378:metabolism / Q000473:pathology; D019683:Penetrance; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D011922:Rats, Mutant Strains; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
D012739:Gonadal Steroid Hormones; D012097:Repressor Proteins; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D004054:Diethylstilbestrol