Fascin表达通常在乳腺癌的某些亚型中观察到,其表达与不良临床结果相关。然而,其在正常乳腺发育中的作用尚未阐明。这里,我们使用fascin基因敲除小鼠模型来评估其在正常乳腺形态发生和泌乳中的作用。Fascin基因敲除不是胚胎致命的,它对出生时产仔数或状况的影响很小。然而,直到断奶阶段的凋落物存活显着取决于仅在护理大坝中的fascin表达。因此,从fascin-/-dams护理的幼崽腹部有较小的乳点,提示哺乳大坝有泌乳缺陷.怀孕和哺乳期fascin-/-小鼠的乳腺整体显示出侧分支和肺泡形成显着减少。尽管有典型的基础成分,管腔,和乳腺细胞的基质亚群以及肌上皮和管腔层的正常导管结构,fascin-/-上皮部分中肺泡祖细胞(ALDH)的百分比显着降低。对fascin-/-乳腺的进一步深入分析显示,肺泡发生的主要调节因子Elf5的表达显着降低,和其下游靶标p-STAT5的活性降低。在协议中,乳蛋白的表达显着减少,乳清酸性蛋白(WAP),和β-酪蛋白在fascin-/-乳腺中。总的来说,我们的数据表明,第一次,fascin在正常乳腺泌乳中的生理作用,一个可以揭示其对乳腺癌发生和进展的贡献的补充。
Fascin expression has commonly been observed in certain subtypes of breast cancer, where its expression is associated with poor clinical outcome. However, its role in normal mammary gland development has not been elucidated. Here, we used a fascin knockout mouse model to assess its role in normal mammary gland morphogenesis and lactation. Fascin knockout was not embryonically lethal, and its effect on the litter size or condition at birth was minimal. However, litter survival until the weaning stage significantly depended on fascin expression solely in the nursing dams. Accordingly, pups that nursed from fascin-/- dams had smaller milk spots in their abdomen, suggesting a lactation defect in the nursing dams. Mammary gland whole-mounts of pregnant and lactating fascin-/- mice showed significantly reduced side branching and
alveologenesis. Despite a typical composition of basal, luminal, and stromal subsets of mammary cells and normal ductal architecture of myoepithelial and luminal layers, the percentage of alveolar progenitors (ALDH+) in fascin-/- epithelial fraction was significantly reduced. Further in-depth analyses of fascin-/- mammary glands showed a significant reduction in the expression of Elf5, the master regulator of
alveologenesis, and a decrease in the activity of its downstream target p-STAT5. In agreement, there was a significant reduction in the expression of the milk proteins, whey acidic protein (WAP), and β-casein in fascin-/- mammary glands. Collectively, our data demonstrate, for the first time, the physiological role of fascin in normal mammary gland lactogenesis, an addition that could reveal its contribution to breast cancer initiation and progression.