Abstract 858: Transplacental cancer prevention by indole-3-carbinol via estrogen receptor beta
Authors: Abby D. Benninghoff, Trevor Fish, Brittany C. Packard, David J. Castro, Lyndsey E. Shorey, David E. Williams
Journal: Cancer Research (2011)

Abstract Indole-3-carbinol (I3C), a key active component of cruciferous vegetables, was recently shown to be an effective anticancer agent when administered transplacentally to mice via the maternal diet. The chemopreventive properties of I3C can involve multiple mechanisms of action, including interaction with the aryl hydrocarbon receptor (AhR) and the estrogen receptor (ER). In this prior transplacental cancer study, the chemopreventive property of I3C was not dependent on the AhR. In the present study, the therapeutic efficacy of I3C in prevention of cancer in offspring exposed in utero to the environmental carcinogen dibenzo[a,l]pyrene (DBP) was evaluated using an ER beta knockout mouse model. B6129SF1/J-Esr2+/- dams and sires were crossed to generate offspring that were either wild-type, heterozygous or null for ER beta. Dams were initiated with 15 mg/kg DBP or sham (corn oil) on gestation day 17. Three experimental diets were evaluated as follows: group 1, dams and offspring were fed control diet throughout the study; group 2, dams were fed 2000 ppm I3C from gestation day 9 through lactation (I3C-GL); and group 3, offspring were fed 2000 ppm I3C from weaning until 6 months of age (I3C-PW). As previously observed, offspring in the DBP-initiated control group developed T-cell lymphoblastic lymphoma by 20 weeks of age, whereas mice in the I3C-GL group were less likely to succumb to the disease (p&amp;lt;0.0001). Although I3C did not reduce incidence of lung cancer in the surviving offspring, lung tumor multiplicity in mice exposed to I3C during gestation and lactation (I3C-GL) was significantly reduced compared to control (p&amp;lt;0.05). I3C administered directly to the offspring (I3C-PW) did not provide protection against DBP-dependent lymphoma or reduce lung tumor multiplicity. This observation points to the critical gestation/lactation window of exposure for chemoprevention by this compound. A significant effect of ER beta genotype was observed in offspring exposed to I3C during gestation and lactation, only. Lymphoma-related mortality was very low in offspring expressing one or both copies of ER beta (+/-, 89% survival; +/+, 96% survival), whereas mortality in offspring lacking ER beta was significantly higher (−/-, 58% survival; p=0.0001.) Interestingly, in this diet group, lung tumor multiplicity in ER beta null offspring was significantly lower than wild-type or heterozygous mice. Collectively, these findings suggest that I3C acts via ER beta to exert its anticancer effects when administered transplacentally to offspring via the maternal diet. Supported by grants F32ES014777, P01CA090890 and the Linus Pauling Institute. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 858. doi:10.1158/1538-7445.AM2011-858