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 shortterm 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. breast cancer protection; hormone; pregnancy BREAST CANCER IS ONE OF THE most common cancers in women and affects nearly 10% of all women in US. In the year 2009, 192,370 new cases of invasive and 62,280 new cases of in situ breast cancer were estimated to have occurred, with 40,170 estimated deaths (3). Various epidemiological studies have revealed that multiple factors including hormones, genetics, reproductive history, radiation, socio-economic status, place of residence, ethnicity, and the environment affect the incidence of breast cancer (9,19,28,29,50,51,60). It has been shown that full-term pregnancy early in life has a protective effect on women against the risk of breast cancer irrespective of genetic background, age, race, or ethnic background (2,37,39,40,64,65,72). For instance, Lambe et al. (1996) (39, 40) and Albrektsen et al. (2005) (2) reported that full-term gestation in a woman younger than 24 yr of age reduces her lifetime risk of developing breast cancer, and this parity-induced protection against breast cancer is significantly affected by the total number of pregnancies. The epidemiological data on breastfeeding and breast cancer risk in humans also show that prolonged breast-feeding confers additional protection against breast cancer (17). However, aborted pregnancies are not associated with decreased risk for breast cancer (8).A ...

Postpartum breast involution reveals regression of secretory lobules mediated by tissue-remodeling

“…However, by 18 months postpartum the lobular area of the gland was indistinguishable from the pattern observed in nulliparous women ( P  = 0.25). It is well documented that in addition to an increase in lobular area, there is increased lobular complexity with pregnancy and lactation [39,45-47] and, as expected, with pregnancy we found the lobular type composition to be highly shifted to type 3 and type 4 differentiated lobules, with evidence for further maturation to type 4 lobules with lactation (n = 151) (Figure  3B and Additional file 4: Figure S2b). As with lobular area, by 18 months postpartum, lobular type composition of the parous group was indistinguishable from the nulliparous group ( P ≥0.65) (Figure  3B).…”

Decreasing Birth Rate Determining Worldwide Incidence and Regional Variation of Female Breast Cancer

“…These findings have driven a hypothesis that oxytocin may have therapeutic effects on cancer [28]. Similarly, Misra et al (2012) reported that females with greater parity may reduce their long-term BCa risk because of multiple hormones released during pregnancy that generate genetic changes in the mammary glands which decrease BCa risk in mature breast cells [31].…”

Pregnancy hormonal environment and mother’s breast cancer risk

“…Thus, although mammary epithelium undergoes extensive changes during pregnancy, lactation, and involution, these changes do not permanently alter mammary epithelial morphology. However, pregnancy leads to a sustained increase in the size of the stroma, and consequently, the ratio between the stroma and epithelium is enlarged, compared to nulliparous animals [56] .…”