A human breast cell model of preinvasive to invasive transition
A human breast cell model of preinvasive to invasive transition
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DOI：
10.1158/0008-5472.can-07-2225
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发表时间：
2008-03-01
期刊：
影响因子：
11.2
通讯作者：
Bissell, Mina J.
中科院分区：
文献类型：
--
作者：
Rizki, Aylin;Weaver, Valerie M.;Bissell, Mina J.
人类乳腺癌进展的关键一步是获得侵袭性。人类细胞培养模型明显缺乏研究从侵袭前表型到侵袭表型的转变，因为它可能在体内自发发生。为了描述对这种转变重要的分子变化，我们分离了在三维重组基底膜培养中显示组织极性部分丧失的人乳腺上皮细胞系。这些细胞仍然是非侵袭性的；然而，与非恶性细胞不同的是，它们在培养中表现出通过基底膜获得侵袭性的高倾向。该模型中细胞的基因组畸变率和基因表达谱显示出与原发乳腺肿瘤谱高度相似的特征。该细胞系在三种不同微环境中形成的裸鼠异种移植瘤表现出化生表型，包括鳞状和基本特征，侵袭性细胞表现出较高级别肿瘤的特征。为了发现从侵袭前到侵袭表型的转变过程中功能上的显著变化，我们对侵袭前和侵袭前细胞之间差异表达的基因列表进行了属性图谱聚类分析。我们发现完整的膜蛋白、转录因子、激酶、运输分子和趋化因子高度表达。此外，基质金属蛋白酶MMP9、MMP13、MMP15和MMP17在侵袭性细胞中表达上调。使用基于小干扰RNA的方法，我们发现这些MMPs是侵袭性表型所必需的。这一模型为剖析乳腺细胞在化生环境中获得侵袭性的机制提供了一种新的工具。
A crucial step in human breast cancer progression is the acquisition of invasiveness. There is a distinct lack of human cell culture models to study the transition from preinvasive to invasive phenotype as it may occur "spontaneously" in vivo. To delineate molecular alterations important for this transition, we isolated human breast epithelial cell lines that showed partial loss of tissue polarity in three-dimensional reconstituted basement membrane cultures. These cells remained noninvasive; however, unlike their nonmalignant counterparts, they exhibited a high propensity to acquire invasiveness through basement membrane in culture. The genomic aberrations and gene expression profiles of the cells in this model showed a high degree of similarity to primary breast tumor profiles. The xenograft tumors formed by the cell lines in three different microenvironments in nude mice displayed metaplastic phenotypes, including squamous and basal characteristics, with invasive cells exhibiting features of higher-grade tumors. To find functionally significant changes in transition from preinvasive to invasive phenotype, we performed attribute profile clustering analysis on the list of genes differentially expressed between preinvasive and invasive cells. We found integral membrane proteins, transcription factors, kinases, transport molecules, and chemokines to be highly represented. In addition, expression of matrix metalloproteinases MMP9, MMP13, MMP15, and MMP17 was up-regulated in the invasive cells. Using small interfering RNA-based approaches, we found these MMPs to be required for the invasive phenotype. This model provides a new tool for dissection of mechanisms by which preinvasive breast cells could acquire invasiveness in a metaplastic context.