Membrane and Cytoskeleton Dynamics Group, Cell Dynamics and Compartmentalization Unit, Institut Curie, Centre National de la Recherche Scientifique UMR144, Paris, France.
Mammalian Developmental Epigenetics Group, Genetics and Developmental Biology Unit, Institut Curie, Paris, France.
Oncogene. 2016 Jan 21;35(3):344-57. doi: 10.1038/onc.2015.87. Epub 2015 Apr 20.
The transition of ductal carcinoma in situ (DCIS) to invasive breast carcinoma requires tumor cells to cross the basement membrane (BM). However, mechanisms underlying BM transmigration are poorly understood. Here, we report that expression of membrane-type 1 (MT1)-matrix metalloproteinase (MMP), a key component of the BM invasion program, increases during breast cancer progression at the in situ to invasive breast carcinoma transition. In the intraductal xenograft model, MT1-MMP is required for BM transmigration of MCF10DCIS.com breast adenocarcinoma cells and is overexpressed in cell clusters overlying focal BM disruptions and at the invasive tumor front. Mirrored upregulation of p63 and MT1-MMP is observed at the edge of MCF10DCIS.com xenograft tumors and p63 is required for induction of MT1-MMP-dependent invasive program in response to microenvironmental signals. Immunohistochemistry and analysis of public database reveal that p63 and MT1-MMP are upregulated in human basal-like breast tumors suggesting that p63/MT1-MMP axis contributes to progression of basal-like breast cancers with elevated p63 and MT1-MMP levels.
导管原位癌 (DCIS) 向浸润性乳腺癌的转变需要肿瘤细胞穿过基底膜 (BM)。然而，BM 迁移的机制尚不清楚。在这里，我们报告膜型 1 (MT1)-基质金属蛋白酶 (MMP) 的表达在原位至浸润性乳腺癌转变过程中在乳腺癌进展过程中增加，MT1-MMP 是 BM 浸润程序的关键组成部分。在腔内异种移植模型中，MT1-MMP 是 MCF10DCIS.com 乳腺腺癌细胞 BM 迁移所必需的，并且在局灶性 BM 破坏上方的细胞簇和浸润性肿瘤前缘过度表达。在 MCF10DCIS.com 异种移植肿瘤的边缘观察到 p63 和 MT1-MMP 的镜像上调，并且 p63 是对微环境信号响应诱导 MT1-MMP 依赖性浸润程序所必需的。免疫组织化学和公共数据库分析表明，p63 和 MT1-MMP 在人基底样乳腺癌中上调，提示 p63/MT1-MMP 轴有助于具有升高的 p63 和 MT1-MMP 水平的基底样乳腺癌的进展。
