Abrupt involution induces inflammation, estrogenic signaling, and hyperplasia linking lack of breastfeeding with increased risk of breast cancer
Abrupt involution induces inflammation, estrogenic signaling, and hyperplasia linking lack of breastfeeding with increased risk of breast cancer
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DOI：
10.1186/s13058-019-1163-7
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发表时间：
2019-07-17
影响因子：
7.4
通讯作者：
Ramaswamy, Bhuvaneswari
中科院分区：
文献类型：
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作者：
Basree, Mustafa M.;Shinde, Neelam;Ramaswamy, Bhuvaneswari
背景：一项对47项流行病学研究数据的大型协作分析得出结论，母乳喂养持续时间越长，患乳腺癌的风险越低。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之间的分子机制仍不清楚。方法：我们在野生型FVB/N小鼠中模拟了两种类型的母乳喂养行为：(1)长期母乳喂养后乳腺组织正常或逐渐退化；(2)短期母乳喂养后强迫或突然退化。为了做到这一点，小鼠在28到31天之间逐渐断奶(逐渐退缩)或在产后7天突然断奶(突然退缩)。用免疫组织化学方法检测乳腺的组织学变化、增殖和炎症标志物。采用荧光激活细胞分选法对乳腺上皮细胞亚群进行定量。基因集浓缩分析用于分析小鼠乳腺造血祖细胞的基因表达数据。类似的分析使用了从组织收集研究OSU-2011C0094登记的产妇的乳房样本中产生的基因表达数据，这些妇女正在接受乳房缩小整形手术，没有乳腺癌病史。结果：与逐渐退缩的小鼠相比，突然退缩的小鼠的乳腺间质致密，胶原成分改变，炎症和增殖增加，雌激素受体α和孕激素受体的表达增加。重要的是，当出生后4个月时，处于突然退化队列中的小鼠出现了导管增生和鳞状化生。突然退化还导致与Notch和雌激素信号通路基因丰富相关的腔前体细胞室的显着扩张。从母乳喂养6个月的健康女性获得的乳腺组织显示，Notch信号通路基因显著丰富，并有丰富管腔祖细胞基因特征的趋势，这与BRCA1突变携带者和基底样乳腺肿瘤中观察到的情况类似。结论：我们首次报道了怀孕后乳腺被迫或突然退化以及缺乏母乳喂养导致管腔前体细胞扩张、更高的炎症、增殖和导管增生，这是已知的乳腺癌发展的危险因素。
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 7days 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 alpha and progesterone receptor expression compared to those that underwent gradual involution. Importantly, when aged to 4months 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 = 6months 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.