The role of JNK2 and JNK1 in breast cancer mediated invasion and metastasis

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Title: The role of JNK2 and JNK1 in breast cancer mediated invasion and metastasis
Author: Nasrazadani, Azadeh
Abstract: Receptor tyrosine kinase (RTK ) inhibitors are emerging as an effective therapeutic option for treatment of breast cancer patients overexpressing particular RTKs . However , more patients may benefit from an inhibitor targeting a common effector protein downstream several RTKs . The presented studies herein identify c -Jun N -Terminal Kinase 2 (JNK2 ) , a kinase downstream multiple RTKs , as a novel target to effectively inhibit Phosphatidylinositol 3 -kinase /AKT activation and metastasis . Knockdown of JNK2 in the highly metastatic 4T1 .2 mammary cancer cells significantly decreased growth factor induced invasion in Boyden chambers , orthotopic tumor growth , and metastatic lesions in lungs and bone . Intra -cardiac introduction of cancer cells is utilized to specifically study the later steps in the metastatic cascade including travel of disseminated cancer cells to a secondary location . Thus , earlier steps such as the process of acquiring a malignant phenotype leading to escape from the primary tumor are bypassed . Survival was prolonged in mice receiving intra -cardiac injection of cells deficient of JNK2 either in the host or in the tumor cells , suggesting a potential role for JNK2 as a therapeutic target for advanced stage breast cancer patients . Using siRNA and inhibitors against Src and PI3K , we determined that JNK2 activity is dependent on Src and PI3K , positioning JNK2 downstream of two critical factors involved in tumor progression . Microarray analysis of JNK2 deficient tumors revealed that JNK2 positively regulates the adaptor protein Grb2 associated binding protein 2 (Gab2 ) . Knockdown of Gab2 in 4T1 .2 cells resulted in decreased tumor growth and a trend for decreased lung metastasis . In vitro , stimulation of 4T1 .2 shJNK2 or 4T1 .2 shGab2 cells with HGF , heregulin , or insulin resulted in impaired AKT activation , suggesting involvement of Gab2 and JNK2 in multiple RTK signaling pathways . Understanding of the intricate mechanisms involved in RTK signal transduction can contribute to drug design geared towards more effective targets , namely JNK2 . The secondary goal of this research was to decipher the individual roles of JNK2 and JNK1 in metastatic breast cancer . Survival was significantly shortened in mice injected intra -cardiac with 4T1 .2 shJNK1 cells . In congruence , serum Cathepsin K levels were increased and bone lesions observed were higher in mice injected with shJNK1 expressing tumor cells compared to mice injected with control cells . In sharp contrast , jnk1 - / - mice displayed dramatically increased survival and fewer bone lesions upon intra -cardiac injections of 4T1 .2 cells . Collectively , these data suggest cell and isoform specific roles for JNKs .
URI: http : / /hdl .handle .net /2152 /ETD -UT -2010 -08 -1576
Date: 2010-10-27


The role of JNK2 and JNK1 in breast cancer mediated invasion and metastasis. Doctoral dissertation, University of Texas at Austin. Available electronically from http : / /hdl .handle .net /2152 /ETD -UT -2010 -08 -1576 .

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