Pregnancy hormonal environment and mother’s breast cancer risk

Abstract

Pregnancy can both reduce and increase lifetime breast cancer risk, and it also induces a short-term, transient increase in risk. Several biological mechanisms have been proposed to explain the protective effect, including pregnancy-induced increase in circulating estrogen levels leading to reduced estrogen receptor (ER) expression and activity. Persistent changes in ER-regulated gene expression may then alter the response of the breast to postpregnancy hormonal exposures originating, for example, from food. Understanding how pregnancy increases breast cancer risk has received less attention. Human studies indicate that those women who were exposed to an elevated pregnancy estrogenic environment, such as women who took the synthetic estrogen diethylstilbestrol or who had the highest circulating estrogen levels at the beginning or end of pregnancy, are at increased risk of developing breast cancer. There is also evidence that elevated leptin levels, for example, in pregnant women who gained excessive amount of weight, increase later breast cancer risk. This may reflect a close interaction between estradiol (E2), ER, and leptin. Our preclinical study suggests that an exposure to excess pregnancy E2 and leptin levels reverses the protective changes in genomic signaling pathways seen in the breast/mammary gland of parous women and rodents. Recent findings indicate that involution - the period after lactation when the breast regresses back to prepregnancy stage - may be related to some pregnancy-associated breast cancers. Importantly, in a preclinical model, the increase can be reversed by anti-inflammatory treatment, offering hope that the increase in lifelong breast cancer risk induced by late first pregnancy or by an exposure of pregnant women to an excessive hormonal environment may be reversible.

Gestational Age and the Risk of Maternal Breast Cancer: A Population-Based Case-Control Study

“…Relatively high levels of estrogen during pregnancy are frequently viewed as the primary reason . Breast cells undergo extensive changes in pregnancy due to variations in hormonal levels which predisposes them to malignant transformation . Several pregnancy characteristics are thought to confound this link or influence the risk of maternal breast cancer independently.…”

Effects of Maternal Grape Juice Intake on Unfolded Protein Response in the Mammary Glands of Offspring of High Fat Diet Fed Rat Dams

“…TEBs contain a high number of mammary stem cells and proliferating epithelial cells, both of which are vulnerable to transformation into malignant cells [47]. As we have previously reported [14,15,48], maternal HFD that led to increased mammary cancer risk also increased TEBs in the offspring's mammary glands. Consumption of grape juice by pregnant dams eliminated this difference in TEBs in the HFD offspring.…”

Exposures to Synthetic Estrogens at Different Times During the Life, and Their Effect on Breast Cancer Risk

“…Using a preclinical rodent model we have investigated whether an exposure to E2 during pregnancy alters gene signaling in the dam’s mammary gland [195]. The analysis of gene expression patterns by microarrays and verification by PCR indicate that pregnancy E2 exposure reverses the reported protective changes in several genes induced by pregnancy, which have been observed in both rodent models and humans, including transforming growth factor β3 (TGFβ3).…”