Signaling events mediated by α3β1 integrin are essential for mammary tumorigenesis.
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.
1] Institut Curie, Centre de Recherche, Paris, France [2] Section de Recherche, UMR144 Centre National de la Recherche Scientifique-Institut Curie, Paris, France.
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Cagnet
1] Institut Curie, Centre de Recherche, Paris, France [2] Section de Recherche, UMR144 Centre National de la Recherche Scientifique-Institut Curie, Paris, France.
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Faraldo
Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
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Kreft
Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
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Sonnenberg
1] Institut Curie, Centre de Recherche, Paris, France [2] Section de Recherche, UMR144 Centre National de la Recherche Scientifique-Institut Curie, Paris, France.
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Raymond
1] Institut Curie, Centre de Recherche, Paris, France [2] Section de Recherche, UMR144 Centre National de la Recherche Scientifique-Institut Curie, Paris, France.
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Glukhova
D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D039201:Integrin alpha3beta1 / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009368:Neoplasm Transplantation; D018295:Neoplasms, Basal Cell / Q000378:metabolism* / Q000473:pathology; D009479:Neuropeptides / Q000378:metabolism; D015533:Transcriptional Activation; D054462:p21-Activated Kinases / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
D039201:Integrin alpha3beta1; D009479:Neuropeptides; C484602:Rac1 protein, mouse; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse; C515905:Pak1 protein, mouse; D054462:p21-Activated Kinases; D020928:Mitogen-Activated Protein Kinases; D020830:rac1 GTP-Binding Protein