Werb Z, Sympson C J, Alexander C M, Thomasset N, Lund L R, MacAuley A, Ashkenas J, Bissell M J
Laboratory of Radiobiology and Environmental Health, University of California, San Francisco, USA.
Kidney Int Suppl. 1996 May;54:S68-74.
An intact basement membrane is essential for the proper function, differentiation and morphology of many epithelial cells. The disruption or remodeling of the basement membrane occurs during normal development as well as in the disease state. To examine the importance of basement membrane during development in vivo, we altered the matrix metalloproteinase and tissue inhibitor of metalloproteinases balance in mammary gland. Inhibition of matrix metalloproteinase synthesis by glucocorticoids or implants or transgenic overexpression of tissue inhibitor of metalloproteinases -1 delays matrix degradation and the involution process after weaning. The mammary glands from transgenic mice that inappropriately express auto-activating isoforms of stromelysin-1 are both functionally and morphologically altered throughout development. Transgenic mammary glands have supernumerary branches, and show precocious development of alveoli that express beta-casein expression and undergo unscheduled apoptosis during pregnancy. This is accompanied by progressive development of an altered stroma, which becomes fibrotic after postweaning involution, and by development of neoplasias. These data suggest that metalloproteinases and disruption of the basement membrane may play key roles in branching morphogenesis of mammary gland, cell cycle, apoptosis, and stromal fibrosis as well as in induction and progression of breast cancer.
完整的基底膜对于许多上皮细胞的正常功能、分化和形态至关重要。基底膜的破坏或重塑在正常发育过程以及疾病状态下都会发生。为了研究体内发育过程中基底膜的重要性，我们改变了乳腺中基质金属蛋白酶和金属蛋白酶组织抑制剂的平衡。糖皮质激素抑制基质金属蛋白酶合成、植入物或金属蛋白酶组织抑制剂-1的转基因过表达会延迟断奶后基质降解和 involution 过程。在整个发育过程中，不适当表达基质溶解素-1 自激活异构体的转基因小鼠的乳腺在功能和形态上都会发生改变。转基因乳腺有多余的分支，并显示出表达β-酪蛋白的肺泡早熟发育，在怀孕期间经历非程序性细胞凋亡。这伴随着改变的基质的逐渐发展，断奶后 involution 时基质会变成纤维化，同时伴随着肿瘤的发展。这些数据表明，金属蛋白酶和基底膜的破坏可能在乳腺的分支形态发生、细胞周期、细胞凋亡、基质纤维化以及乳腺癌的诱导和进展中起关键作用。
