NDLI: Interaction between genetic susceptibility and early-life environmental exposure determines tumor-suppressor-gene penetrance

Content Provider	PubMed Central
Author	Cook, Jennifer D. Davis, Barbara J. Cai, Sheng-li Barrett, J. Carl Conti, Claudio J. Walker, Cheryl Lyn
Copyright Year	2005
Abstract	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.
Related Links	http://dx.doi.org/10.1073/pnas.0503218102
Starting Page	8644
File Format	PDF
ISSN	10916490
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	24
Volume Number	102
Language	English
Publisher	National Academy of Sciences
Publisher Date	2005-06-14
Access Restriction	Open
Rights Holder	National Academy of Sciences
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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