Fetal Alcohol Exposure and Mammary Tumorigenesis in Offspring: Role of the Estrogen and Insulin-Like Growth Factor Systems

Abstract

Fetal alcohol spectrum disorders affect a significant number of live births each year, indicating that alcohol consumption during pregnancy is an important public health issue. Environmental exposures and lifestyle choices during pregnancy may affect the offspring's risk of disease in adulthood, leading to the idea that a woman's risk of breast cancer may be pre-programmed prior to birth. Exposure of pregnant rats to alcohol increases tumorigenesis in the adult offspring in response to mammary carcinogens. The estrogen and insulin-like growth factor (IGF-I) axes occupy central roles in normal mammary gland development and breast cancer. 17-β estradiol (E2) and IGF-I synergize to regulate formation of terminal end buds and ductal elongation during pubertal development. The intracellular signaling pathways mediated by the estrogen and IGF-I receptors cross-talk at multiple levels through both genomic and non-genomic mechanisms. Several components of the E2 and IGF-I systems are altered in early development in rat offspring exposed to alcohol in utero, therefore, these changes may play a role in the enhanced susceptibility to mammary carcinogens observed in adulthood. Alcohol exposure in utero induces a number of epigenetic alterations in non-mammary tissues in the offspring and other adverse in utero exposures induce epigenetic modifications in the mammary gland. Future studies will determine if fetal alcohol exposure can induce epigenetic modifications in genes that regulate E2/IGF action at key phases of mammary development, ultimately leading to changes in susceptibility to carcinogens.

Parents ethanol use impairs ethanol-naive offspring development and reproduction

“…Since estradiol levels were similar in the groups, we associated the delay puberty onset with reduced ovarian mass and we hypothesized an inadequate response between ovarian receptors and gonadotrophic hormones. The decrease of the IGF could be an additional factor for reproductive impairment in females (Cohick et al 2015).…”

Alcohol�s Effects on Breast Cancer in Women

“…Evidence from animal models indicates that ethanol exposure in utero can lead to increased breast tumorigenesis in the adult offspring when exposed to carcinogens. 33 These studies indicate that the association of lifetime alcohol consumption with breast cancer risk may be different depending on when the alcohol was consumed. Evidence shows, with some inconsistency among studies, that consumption in adolescence and before a first pregnancy may particularly affect risk.…”

In utero exposure to carcinogens: Epigenetics, developmental disruption and consequences in later life

“…In females, 17-β-oestradiol (E2) and IGF-1 synergise to regulate formation of terminal end buds and ductal elongation during breast development in puberty and there is cross-talk between the intracellular signalling pathways mediated by the E2 and IGF-1 receptors. Both genomic and non-genomic mechanisms are involved [14]. If alcohol exposure in utero induces epigenetic modifications, probably via its known interactions with miRNAs [15], then this may lead to a cascade process where susceptibility to breast cancer is increased in later life…”