1] Institut Curie, Centre de Recherche, Paris, France [2] Section de Recherche, UMR144 Centre National de la Recherche Scientifique-Institut Curie, Paris, France.
Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Oncogene. 2014 Aug 21;33(34):4286-95. doi: 10.1038/onc.2013.391. Epub 2013 Sep 30.
The constitutive activation of β-catenin signaling in the mammary basal epithelial cell layer in transgenic K5ΔNβcat mice leads to basal-type tumor development. Integrins of the β1 family and integrin-mediated signaling events have an important role in breast tumor growth and progression. We show here that the deletion of α3β1 integrin, a major laminin receptor, from the basal layer of the mammary epithelium of K5ΔNβcat mice completely prevented the tumorigenesis induced by β-catenin signaling. Moreover, the depletion of α3β1 integrin from a spontaneously transformed mouse mammary basal epithelial cell line (MEC) prevented the cells from forming colonies in soft agar and greatly reduced tumor development in orthotopic grafts. Inhibition of the integrin signaling intermediates Rac1 or PAK1 (P21-activated Kinase 1) in MEC affected tumor cell growth in soft agar, whereas the expression of activated forms of these effectors in α3-depleted cells rescued the capacity of these cells to grow in non-adherent conditions. Similarly, the tumorigenic potential of α3-depleted cells was restored by the expression of activated PAK1, as assessed by orthotopic transplantation assay. In three-dimensional Matrigel culture, MEC survival and proliferation were affected by the depletion of α3β1 integrin, which also significantly decreased the activation of focal adhesion kinase (FAK), mitogen-activated protein kinase (MAPK) and c-Jun NH2-terminal kinase (JNK). Our data suggest that the activation of signaling cascades downstream from α3β1 and involving the Rac1/PAK1 pathway, MAPK and JNK, promotes prosurvival and proproliferative signals required for the malignant growth of basal mammary epithelial cells, providing further insight into the molecular mechanisms underlying breast cancer initiation and progression.
在 K5ΔNβcat 转基因小鼠的乳腺基底上皮细胞层中，β-连环蛋白信号的组成性激活导致基底型肿瘤的发展。β1 家族整联蛋白和整联蛋白介导的信号事件在乳腺肿瘤的生长和进展中起着重要作用。我们在这里表明，从 K5ΔNβcat 小鼠乳腺上皮基底层中缺失主要的层粘连蛋白受体α3β1 整联蛋白，完全阻止了β-连环蛋白信号诱导的肿瘤发生。此外，从自发转化的小鼠乳腺基底上皮细胞系（MEC）中耗尽α3β1 整联蛋白，可防止细胞在软琼脂中形成集落，并大大减少同源移植中的肿瘤发生。在 MEC 中抑制整联蛋白信号中间产物 Rac1 或 PAK1（P21 激活激酶 1），可影响软琼脂中肿瘤细胞的生长，而在α3 耗尽细胞中表达这些效应物的激活形式，则可恢复这些细胞在非贴壁条件下生长的能力。同样，通过表达激活的 PAK1，也可恢复α3 耗尽细胞的致瘤潜能，这可通过同源移植测定来评估。在三维 Matrigel 培养中，MEC 的存活和增殖受到α3β1 整联蛋白耗竭的影响，这也显著降低了粘着斑激酶（FAK）、丝裂原激活蛋白激酶（MAPK）和 c-Jun NH2-末端激酶（JNK）的激活。我们的数据表明，α3β1 下游信号通路的激活，涉及 Rac1/PAK1 途径、MAPK 和 JNK，促进了生存和增殖信号的激活，这些信号是基底乳腺上皮细胞恶性生长所必需的，为乳腺癌发生和进展的分子机制提供了进一步的认识。
