Mammary gland morphological and gene expression changes underlying pregnancy protection of breast cancer tumorigenesis.
ABSTRACT A full-term pregnancy early in life reduces lifetime risk of developing breast cancer, and the effect can be mimicked in rodents by full-term pregnancy or short-term treatment with exogenous estrogen and progesterone. To gain insight into the protective mechanism, 15 3-mo-old postpubertal virgin Lewis rats were randomly assigned to three groups: control (C), pregnancy (P), or hormone (H). The P group animals underwent a full-term pregnancy, and H group animals were implanted subcutaneously with silastic capsules filled with ethynyl estradiol and megesterol acetate for 21 days. C and P animals were implanted with sham capsules. On day 21 capsules were removed, which was followed by a 49-day involution period, euthanasia, and mammary tissue collection. Global gene expression was measured using Rat Genome 230.2 Arrays. Histological analysis revealed that P and H treatments induced sustained morphological changes in the mammary gland with significantly increased percentages of mammary parenchyma and stromal tissues and higher ratio of stroma to parenchyma. Transcriptome analysis showed that P and H treatments induced sustained global changes in gene expression in the mammary gland. Analysis of commonly up- and downregulated genes in P and H relative to C treatment showed increased expression of three matrix metallopeptidases (Mmp3, 8, and 12), more differentiated mammary phenotype, enhanced innate and adaptive immunity, and reduced cell proliferation and angiogenic signatures. The sustained morphological and global gene expression changes in mammary tissue after pregnancy and hormone treatment may function together to provide the protective effect against breast cancer.
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ABSTRACT: Pregnancy can both reduce and increase lifetime breast can-cer 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 expo-sures 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 diethylstil-bestrol 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 refl ect 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 fi ndings indicate that involution – the period after lac-tation when the breast regresses back to prepregnancy stage – may be related to some pregnancy-associated breast can-cers. Importantly, in a preclinical model, the increase can be reversed by anti-infl ammatory treatment, offering hope that the increase in lifelong breast cancer risk induced by late fi rst pregnancy or by an exposure of pregnant women to an exces-sive hormonal environment may be reversible.Hormone molecular biology and clinical investigation 01/2012;