Crk adaptor proteins act as key signaling integrators in breast cancer development and metastasis

• Main Author: Fathers, Kelly
• Other Authors: Park, Morag (Supervisor)
• Format: Others
• Language: en
• Published: McGill University 2009
• Subjects: Biochemistry
• Online Access: http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=95621

The Crk adaptor proteins (CrkI, CrkII and CrkL) play an important role during cellular signalling by mediating the formation of prote in complexes. We examined the function of Crk in cancer by examining how the loss of Crk would affect tumor progression using RNA interference, as well as examining the consequences of Crk overexpression. For each cancer cellline tested, loss of Crk expression corresponded with a significant decrease in cell migration, invasion, and adhesion, demonstrating that Crk adaptor proteins play an important role in integrating signaIs of highly malignant cancer cell lines. This has important implications as elevated levels of Crk are observed in human cancers. To formally test this in vivo, stable knockdown of Crk using an shRNA mediated approach was obtained in breast cancer celllines that have a high propensity to form bone metastases (MDA-231 1833TR). Loss of Crk was associated with a significant decrease in the formation of bone metastases, as weIl as growth at both the primary and secondary site. Loss of Crk was associated with decreases in Rac and Cdc42 activation as weIl as other signaling proteins. These data demonstrate that Crk adaptor proteins may play a role in breast cancer progression, however whether Crk proteins can lead to breast cancer development has not been addressed. To test this, transgenic mouse models that allow the over-expression of CrkII in the mammary epithelium through the MMTV promoter were established. [...] === Les protéines adaptatrices Crk (CrkI, CrkII et CrkL) jouent un rôle important dans la signalisation intracellulaire en médiant la formation de complexes protéiques. Nous avons étudié le rôle de Crk dans le processus cancéreux en évaluant en quoi la perte de Crk affectait la progression tumorale, et ce grâce à l'utilisation d'ARN interférence. Pour chaque lignée cellulaire tumorale testée, la perte d'expression de Crk s'est avérée associée à une réduction significative de la migration, de l'invasion et de l'adhésion cellulaire, démontrant que les protéines adaptatrices Crk jouent un rôle important dansl'intégration de signaux dans le cadre de lignées cellulaires cancéreuses de haute malignité. Ces résultats ont un impact important puisque des niveaux d'expression élevés de Crk sont observés dans de nombreux cancers humains. Nous avons alors généré des "knock-down" stables de Crk via la méthode de shRNA dans une lignée cellulaire issue de carcinome mammaire qui a une forte propension à former des métastases osseuses (MDA-231 1833TR). La perte de Crk s'est révélée associée à une réduction de la formation de métastases osseuses, mais aussi du développement tumoral aux sites primaires et secondaires. [...]