Maternal Dioxin Exposure Combined with a Diet High in Fat Increases Mammary Cancer Incidence in Mice

Total lifetime exposure to estrogen (E2) is the single greatest environmental risk factor for breast cancer (Dunn et al. 2005). The classic pathway of E2-mediated carcinogenesis is through the estrogen receptor (ER), where E2 alters gene expression to increase cell proliferation (Currier et al. 2005). Consequently, it has been hypothesized that E2 metabolism acts to decrease breast cancer risk (Holcomb and Safe 1994). Yet, some E2 metabolites may increase breast cancer risk through DNA damage (Cavalieri and Rogan 2004; Cavalieri et al. 1997). E2 is metabolized by cytochrome P450 (CYP) 1B1 into reactive catechols that undergo redox cycling, resulting in oxidative stress, DNA adduct formation, and DNA mutations (Cavalieri and Rogan 2004; Chakravarti et al. 2001; Mitrunen and Hirvonen 2003). The phase II enzyme catechol-O-methyltransferase (COMT) mitigates this genotoxicity by inactivating the E2 catechols via O-methylation. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and other aryl hydrocarbon receptor (AhR) agonists can modulate E2 activity through induction of E2-metabolizing CYP1A1 and CYP1B1 enzymes (Mitrunen and Hirvonen 2003). Thus, TCDD has the potential to modify breast cancer risk through alteration of ER-mediated proliferation or CYP1-mediated DNA damage (Mitrunen and Hirvonen 2003). The influence of TCDD exposure during early-life periods may be more pronounced because early-life estrogenic exposures appear to contribute to a greater risk of breast cancer than do exposures later in life (Dolinoy et al. 2007; Hilakivi-Clarke et al. 1999, 2000). An industrial accident in Seveso, Italy, supports the link between early-life TCDD exposure and cancer risk. TCDD exposure was positively associated with breast cancer risk only in women who were infants up to 40 years of age at the time of the accident (Warner et al. 2002). Early-life TCDD exposure, particularly perinatally, has also been associated with increased mammary tumorigenesis in several rodent models (Brown et al. 1998; Desaulniers et al. 2001). Paradoxically, although greater E2 exposure in adolescents with early menses contributes to increased breast cancer risk (Vihko and Apter 1984), delayed pubertal breast differentiation may also increase breast cancer risk. Rodent models have shown that perinatal TCDD exposure increases mammary tumor risk through altered mammary differentiation (Brown et al. 1998; Fenton et al. 2002), which extends the period in which the rapidly proliferating progenitor cells of the terminal end buds (TEBs) are susceptible to carcinogenic insult (Birnbaum and Fenton 2003). A similar developmental delay has been reported in humans; as serum TCDD concentrations increase in either prenatal or premenarcheal samples, the timing of pubertal breast development is delayed (Den Hond et al. 2002; Leijs et al. 2008). Like TCDD and E2 exposures, obesity may have age-specific or developmental-stage–specific effects on breast cancer risk (De Assis and Hilakivi-Clarke 2006). Obesity may also modify breast cancer risk through increased persistence of lipophilic TCDD in adipose tissue, including mammary stroma (Emond et al. 2006). Consequently, mammary glands of obese individuals are likely exposed to greater TCDD levels than in their lean counterparts (Emond et al. 2006; Harrad et al. 2003; Hooper et al. 1998; Michalek and Tripathi 1999). Because obese individuals retain more TCDD, maternal TCDD exposure may result in altered susceptibility to breast cancer among their offspring. In the present study we used the 7,12-dimethylbenz[a]anthracene (DMBA) mouse model of breast cancer to examine the mechanistic basis of how maternal TCDD exposure and obesity-associated high-fat diets (HFDs) increase cancer risk. We found that the combined effect of maternal TCDD exposure and an HFD increases mammary cancer risk through alterations in metabolism capability and the rate of breast development.