胎儿酒精暴露改变乳腺上皮细胞亚群并促进肿瘤发生。

Fetal Alcohol Exposure Alters Mammary Epithelial Cell Subpopulations and Promotes Tumorigenesis.

机构信息

From the, The Department of Animal Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ.

出版信息

Alcohol Clin Exp Res. 2020 Apr;44(4):831-843. doi: 10.1111/acer.14308. Epub 2020 Mar 4.

DOI:10.1111/acer.14308

PMID:32056248

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7166183/

Abstract

BACKGROUND

Fetal alcohol exposure (FAE) increases the risk of mammary tumorigenesis in adult offspring; however, the underlying mechanism remains unknown. This study tested the hypothesis that FAE shifts the mammary epithelial cell (MEC) composition toward one that promotes tumorigenesis.

METHODS

Pregnant Friend Virus B NIH Jackson dams bred to MMTV-Wnt1 male mice were given ad libitum access to 5% alcohol in 0.2% saccharin solution from GD9-10 and 10% alcohol in 0.2% saccharin from GD11-GD19 or 0.2% saccharin solution from GD9-GD19. Thoracic and inguinal mammary glands from wild-type (WT) and transgenic (Tg) female offspring were harvested at 5 and 10 weeks of age and dissociated to yield a single cell suspension enriched for MECs for flow cytometry, mammosphere assay, and gene analysis. A subset of Tg offspring was followed for tumor formation.

RESULTS

WT glands of FAE animals exhibited a decreased basal cell population and increased luminal: basal ratio at 10 weeks of age. qRT-PCR analysis of total MECs found that Hey1 mRNA expression was increased in the WT FAE group at 10 weeks of age. In Tg glands, FAE increased the luminal progenitor cell population at 5 weeks of age but did not alter MEC composition at 10 weeks of age. Tertiary mammosphere-forming efficiency was greater in the WT glands of FAE animals at 10 weeks of age. Tumor latency was decreased in the FAE group. Flow cytometry analysis indicated that FAE females developed tumors with an increased basal cell population.

CONCLUSIONS

These data indicate that FAE can shift MEC subpopulations, increasing the proportion of cells that are potentially vulnerable to transformation and affecting cancer risk.

摘要

背景

胎儿酒精暴露（FAE）会增加成年后代患乳腺癌的风险；然而，其潜在机制尚不清楚。本研究检验了这样一个假设，即 FAE 会使乳腺上皮细胞（MEC）组成向促进肿瘤发生的方向转变。

方法

妊娠 Friend 病毒 B NIH 杰克逊母鼠与 MMTV-Wnt1 雄性小鼠交配，从 GD9-10 给予自由摄取 5%酒精加 0.2%糖精溶液，从 GD11-GD19 给予 10%酒精加 0.2%糖精溶液，或从 GD9-GD19 给予 0.2%糖精溶液。5 周龄和 10 周龄时，采集野生型（WT）和转基因（Tg）雌性后代的胸和腹股沟乳腺，分离得到富含 MEC 的单细胞悬液，用于流式细胞术、乳腺球体形成试验和基因分析。一部分 Tg 后代被跟踪观察肿瘤形成情况。

结果

FAE 动物的 WT 乳腺在 10 周龄时表现出基底细胞群体减少和腔面：基底比例增加。对总 MEC 的 qRT-PCR 分析发现，WT FAE 组在 10 周龄时 Hey1mRNA 表达增加。在 Tg 乳腺中，FAE 在 5 周龄时增加了腔前体细胞群体，但在 10 周龄时没有改变 MEC 组成。10 周龄时，WT 乳腺的三发性乳腺球体形成效率在 FAE 动物中更高。FAE 组的肿瘤潜伏期缩短。流式细胞术分析表明，FAE 雌性动物的肿瘤具有更高的基底细胞群体。