Perturbation of β1-Integrin Function in Involuting Mammary Gland Results in Premature Dedifferentiation of Secretory Epithelial Cells

To study the mechanism of β1-integrin function in vivo, we have generated transgenic mouse expressing a dominant negative mutant of β1-integrin under the control of mouse mammary tumor virus (MMTV) promoter (MMTV-β1-cyto). Mammary glands from MMTV-β1-cyto transgenic females present significant growth defects during pregnancy and lactation and impaired differentiation of secretory epithelial cells at the onset of lactation. We report herein that perturbation of β1-integrin function in involuting mammary gland induced precocious dedifferentiation of the secretory epithelium, as shown by the premature decrease in β-casein and whey acidic protein mRNA levels, accompanied by inactivation of STAT5, a transcription factor essential for mammary gland development and up-regulation of nuclear factor-κB, a negative regulator of STAT5 signaling. This is the first study demonstrating in vivo that cell–extracellular matrix interactions involving β1-integrins play an important role in the control of milk gene transcription and in the maintenance of the mammary epithelial cell differentiated state.

为在体内探究β1整合素（β1-integrin）的功能机制，我们构建了在小鼠乳腺肿瘤病毒（mouse mammary tumor virus, MMTV）启动子调控下表达β1整合素显性负突变体的转基因小鼠（MMTV-β1-cyto）。MMTV-β1-cyto转基因雌性小鼠的乳腺在妊娠及泌乳阶段均出现显著生长缺陷，且在泌乳启动阶段存在分泌上皮细胞分化受损的表型。本文报道，在退化期乳腺中扰动β1整合素功能会诱导分泌上皮细胞发生早熟去分化，具体表现为β-酪蛋白（β-casein）与乳清酸性蛋白（whey acidic protein）的mRNA水平提前下降，同时伴随乳腺发育必需的转录因子信号转导与转录激活因子5（STAT5）的失活，以及STAT5信号通路负调控因子核因子κB（nuclear factor-κB, NF-κB）的表达上调。本研究首次在体内证实，涉及β1整合素的细胞-细胞外基质相互作用，在调控乳蛋白基因转录以及维持乳腺上皮细胞分化状态中发挥重要作用。