{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T08:38:34Z","timestamp":1792658314370,"version":"4.5.0"},"reference-count":42,"publisher":"National Academy of Sciences","issue":"24","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2005,6,14]]},"abstract":"<jats:p>\n                    Gene\u2013environment interactions are important determinants of cancer risk. Traditionally, gene\u2013environment 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\u2013environment 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 (\n                    <jats:italic>Tsc-2<\/jats:italic>\n                    ) 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 &gt;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\n                    <jats:italic>Tsc-2<\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0503218102","type":"journal-article","created":{"date-parts":[[2005,6,3]],"date-time":"2005-06-03T20:24:58Z","timestamp":1117830298000},"page":"8644-8649","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":89,"title":["Interaction between genetic susceptibility and early-life environmental exposure determines tumor-suppressor-gene penetrance"],"prefix":"10.1073","volume":"102","author":[{"given":"Jennifer D.","family":"Cook","sequence":"first","affiliation":[{"name":"Graduate School of Biomedical Sciences, University of Texas, 6655 Travis Street, Suite 300, Houston, TX 77030; Science Park\u2013Research Division, University of Texas M. D. Anderson Cancer Center, P.O. Box 389, Smithville, TX 78957; AstraZeneca, 35 Gatehouse Drive, Waltham, MA 02451; and Center for Cancer Research, National Cancer Institute, National Institutes of Health, 1 Center Drive, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara J.","family":"Davis","sequence":"additional","affiliation":[{"name":"Graduate School of Biomedical Sciences, University of Texas, 6655 Travis Street, Suite 300, Houston, TX 77030; Science Park\u2013Research Division, University of Texas M. D. Anderson Cancer Center, P.O. Box 389, Smithville, TX 78957; AstraZeneca, 35 Gatehouse Drive, Waltham, MA 02451; and Center for Cancer Research, National Cancer Institute, National Institutes of Health, 1 Center Drive, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheng-Li","family":"Cai","sequence":"additional","affiliation":[{"name":"Graduate School of Biomedical Sciences, University of Texas, 6655 Travis Street, Suite 300, Houston, TX 77030; Science Park\u2013Research Division, University of Texas M. D. Anderson Cancer Center, P.O. Box 389, Smithville, TX 78957; AstraZeneca, 35 Gatehouse Drive, Waltham, MA 02451; and Center for Cancer Research, National Cancer Institute, National Institutes of Health, 1 Center Drive, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Carl","family":"Barrett","sequence":"additional","affiliation":[{"name":"Graduate School of Biomedical Sciences, University of Texas, 6655 Travis Street, Suite 300, Houston, TX 77030; Science Park\u2013Research Division, University of Texas M. D. Anderson Cancer Center, P.O. Box 389, Smithville, TX 78957; AstraZeneca, 35 Gatehouse Drive, Waltham, MA 02451; and Center for Cancer Research, National Cancer Institute, National Institutes of Health, 1 Center Drive, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudio J.","family":"Conti","sequence":"additional","affiliation":[{"name":"Graduate School of Biomedical Sciences, University of Texas, 6655 Travis Street, Suite 300, Houston, TX 77030; Science Park\u2013Research Division, University of Texas M. D. Anderson Cancer Center, P.O. 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