Abstract 5200: Role of MLK3 in breast cancer cell migration and metastasis

Abstract

Abstract Effectively treating breast cancer metastasis is one of the biggest challenges in breast cancer therapy. The overall poor prognosis associated with cancer cell migration to distal organs underscores the critical need to understand the biology of the disease in order to develop more effective therapies. Members of protein kinase family have often been targeted for therapeutic purposes in different types of cancer, including breast cancer, and several protein kinase inhibitors are currently in clinical trials for specific types of cancer. The members of Mixed Lineage Kinases (MLKs) are novel family of MAP3Ks and their physiological function is not known, however, we and others have shown that several of MLK family members activate Jun- N-terminal Kinases (JNKs) and MLK activation regulates survival in neuronal cells. Recently, we have seen that MLK3 is highly expressed in invasive breast cancer cell lines and in primary breast tumors, compared to the normal mammary tissue from same patient. Since MLK3 was initially identified from platelet cell line, CMK11-5, and association of venous thrombosis and occult cancer was recognized almost 140 years ago, we hypothesized that MLK3 or other MLKs are important in proteinase receptor-mediated signaling. Furthermore, the downstream effectors of proteinase receptors (PARs) that mediate the breast cancer cell growth, migration and metastasis to distal organs are currently unknown. We examined the role of MLK3 in thrombin mediated signaling in a highly invasive breast cancer cell line, MDA-MB-231. Thrombin treatment of these cells activated MLK3 kinase in a time dependent manner. MLK3 was activated within 2 minutes of thrombin treatment and the activity peaked at 5 minutes, and was associated with consequent activation of its downstream target JNK. Furthermore, pretreatment of MDA-MB-231 with an MLK inhibitor, CEP-11004 completely blocked thrombin-induced JNK activation. Importantly, we also discovered that thrombin induces MLK-dependent migration in MDA-MB-231 cell line was blocked by MLKs inhibitor, CEP-11004. These results collectively suggest that MLK3 is an important target of proteinase receptors-mediated migration/invasion/metastatic pathways, and help us to identify MLK family members’ inhibitors as viable drugs to treat metastatic breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5200.