BACKGROUND A large collaborative analysis of data from 47 epidemiological studies concluded that longer duration of breastfeeding reduces the risk of developing breast cancer. Despite the strong epidemiological evidence, the molecular mechanisms linking prolonged breastfeeding to decreased risk of breast cancer remain poorly understood. METHODS We modeled two types of breastfeeding behaviors in wild type FVB/N mice: (1) normal or gradual involution of breast tissue following prolonged breastfeeding and (2) forced or abrupt involution following short-term breastfeeding. To accomplish this, pups were gradually weaned between 28 and 31 days (gradual involution) or abruptly at 7 days postpartum (abrupt involution). Mammary glands were examined for histological changes, proliferation, and inflammatory markers by immunohistochemistry. Fluorescence-activated cell sorting was used to quantify mammary epithelial subpopulations. Gene set enrichment analysis was used to analyze gene expression data from mouse mammary luminal progenitor cells. Similar analysis was done using gene expression data generated from human breast samples obtained from parous women enrolled on a tissue collection study, OSU-2011C0094, and were undergoing reduction mammoplasty without history of breast cancer. RESULTS Mammary glands from mice that underwent abrupt involution exhibited denser stroma, altered collagen composition, higher inflammation and proliferation, increased estrogen receptor α and progesterone receptor expression compared to those that underwent gradual involution. Importantly, when aged to 4 months postpartum, mice that were in the abrupt involution cohort developed ductal hyperplasia and squamous metaplasia. Abrupt involution also resulted in a significant expansion of the luminal progenitor cell compartment associated with enrichment of Notch and estrogen signaling pathway genes. Breast tissues obtained from healthy women who breastfed for < 6 months vs ≥ 6 months showed significant enrichment of Notch signaling pathway genes, along with a trend for enrichment for luminal progenitor gene signature similar to what is observed in BRCA1 mutation carriers and basal-like breast tumors. CONCLUSIONS We report here for the first time that forced or abrupt involution of the mammary glands following pregnancy and lack of breastfeeding results in expansion of luminal progenitor cells, higher inflammation, proliferation, and ductal hyperplasia, a known risk factor for developing breast cancer.

中文翻译：

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突然的退化导致炎症，雌激素信号传导和增生，这与缺乏母乳喂养和增加患乳腺癌的风险联系在一起。

背景技术对来自47个流行病学研究的数据进行的大规模协作分析得出的结论是，母乳喂养时间越长，患乳腺癌的风险就越小。尽管有强有力的流行病学证据，但延长母乳喂养与降低乳腺癌风险的分子机制仍知之甚少。方法我们对野生型FVB / N小鼠的两种母乳喂养行为进行了建模：（1）长期母乳喂养后正常或渐进的乳腺组织对合，以及（2）短期母乳喂养后强迫或突然对合。为此，在28至31天之间逐渐断奶（逐渐退化），或在产后7天突然断绝（突然退化）。通过免疫组织化学检查乳腺的组织学变化，增殖和炎性标志物。荧光激活细胞分选用于量化乳腺上皮亚群。基因集富集分析用于分析小鼠乳腺腔祖细胞的基因表达数据。使用从人乳腺样品中获得的基因表达数据进行了类似的分析，这些人乳腺样品来自参加组织收集研究OSU-2011C0094并正在接受减少性乳房成形术且没有乳腺癌史的妇女。结果与进行渐进对合的小鼠相比，经历突然对合的小鼠的乳腺表现出更紧密的基质，改变的胶原蛋白成分，更高的炎症和增殖，雌激素受体α和孕激素受体表达。重要的是，当产后到4个月大时，突然对开队列的小鼠出现了导管增生和鳞状化生。突然的对合也导致与Notch和雌激素信号通路基因的富集相关的腔祖细胞区室的显着扩展。从哺乳时间小于6个月vs≥6个月的健康女性获得的乳房组织显示出Notch信号通路基因的显着富集，以及管腔祖细胞基因签名富集的趋势与在BRCA1突变携带者和基底样乳腺中观察到的相似肿瘤。结论我们首次在此报告，妊娠后强迫或突然发生乳腺内翻以及缺乏母乳喂养导致管腔祖细胞膨胀，炎症，增殖和导管增生增加，