Reciprocal interactions between β1-integrin and epidermal growth factor receptor in three-dimensional basement membrane breast cultures:: A different perspective in epithelial biology
Reciprocal interactions between β1-integrin and epidermal growth factor receptor in three-dimensional basement membrane breast cultures:: A different perspective in epithelial biology
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DOI：
10.1073/pnas.95.25.14821
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发表时间：
1998-12-08
影响因子：
11.1
通讯作者：
Bissell, MJ
中科院分区：
文献类型：
--
作者：
Wang, F;Weaver, VM;Bissell, MJ
锚定和生长因子的独立性是转化表型的主要特征。虽然这两种途径在正常组织中必须共同调节以维持稳态是合乎逻辑的，但这尚未得到直接证明。我们先前已经证明β 1整合素信号的下调可以逆转来自表型正常细胞的人乳腺肿瘤细胞系（T4-2）的恶性行为（HMT-3522），并在三维（3D）基底膜测定中导致生长停滞，其中细胞形成组织样腺泡（14）。我们发现，通过丝裂原活化蛋白激酶（MAPK）途径，β 1整合素和表皮生长因子受体（EGFR）信号传导存在双向交叉调节。在单层（2D）培养物中不发生相互调节。抗体介导的肿瘤细胞中这些受体的抑制或MAPK激酶的抑制诱导了两种受体的伴随下调，随后是生长停滞和正常乳腺组织形态发生的恢复。交叉调节和组织形态发生与EGF诱导的瞬时MAPK激活的衰减相关。为了专门测试EGFR和β 1-整合素的相互依赖性，EGFR在非恶性细胞中过表达，导致形态发生的破坏和β 1-整合素表达的补偿性上调，再次仅在3D中，我们的研究结果表明，当乳腺细胞与基底膜接触时，信号传导通路变得耦合和双向。他们进一步解释了为什么乳腺细胞在单层培养中不能分化，而在单层培养中这些事件大多是解偶联的。此外，在这些途径被错误调节但具有功能的肿瘤细胞亚组中，可以通过操纵任一途径使细胞“正常化”。
Anchorage and growth factor independence are cardinal features of the transformed phenotype. Although it is logical that the two pathways must be coregulated in normal tissues to maintain homeostasis, this has not been demonstrated directly. We showed previously that down-modulation of beta 1-integrin signaling reverted the malignant behavior of a human breast tumor cell line (T4-2) derived from phenotypically normal cells (HMT-3522) and led to growth arrest in a three-dimensional (3D) basement membrane assay in which the cells formed tissue-like acini (14), Here, we show that there is a bidirectional cross-modulation of beta 1-integrin and epidermal growth factor receptor (EGFR) signaling via the mitogen-activated protein kinase (MAPK) pathway. The reciprocal modulation does not occur in monolayer (2D) cultures, Antibody-mediated inhibition of either of these receptors in the tumor cells, or inhibition of MAPK kinase, induced a concomitant downregulation of both receptors, followed by growth-arrest and restoration of normal breast tissue morphogenesis, Cross-modulation and tissue morphogenesis were associated with attenuation of EGF-induced transient MAPK activation. To specifically test EGFR and beta 1-integrin interdependency, EGFR was overexpressed in nonmalignant cells, leading to disruption of morphogenesis and a compensatory up-regulation of beta 1-integrin expression, again only in 3D, Our results indicate that when breast cells are spatially organized as a result of contact with basement membrane, the signaling pathways become coupled and bidirectional. They further explain,why breast cells fail to differentiate in monolayer cultures in which these events are mostly uncoupled. Moreover, in a subset of tumor cells in,which these pathways are misregulated but functional, the cells could be "normalized" by manipulating either pathway.