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Targeting JNK to Block Breast Cancer Proliferation and Metastasis
Tumor Cell Biology I
Since the ability of a tumor to metastasize is the major determinant of cancer patient mortality, elucidating the molecular pathways critical for tumor metastasis is a high priority in cancer research. Recently, we found that inhibiting c-Jun N-terminal kinase (JNK) blocked proliferation, migration, and invasion of all tested human and mouse breast cancer cell lines in vitro . In addition, examination of JNK activation in several mouse mammary tumor cell sublines that were isolated from the same primary mouse mammary tumor but show different metastatic potential, revealed that the highly metastatic subline (4T1) exhibited high constitutive JNK activation. On the basis of this evidence, and the fact that the function of JNK in breast cancer progression has been largely overlooked, we hypothesize that JNK is a signaling integrator and coordinator in breast cancer metastasis. Thus, inhibition of JNK may block breast cancer metastasis triggered by various signals, while aberrant JNK activity may lead to a higher metastatic potential in breast cancer cells. We will test our hypothesis in the following specific aims. 1) To determine whether inhibition of JNK in vivo blocks breast cancer invasion and metastasis. We will inhibit JNK activity in the highly metastatic mouse mammary tumor cell line 4T1 and inject the cells into mammary ducts or fat pads of syngeneic wildtype BALB/c mice. Cells will be fluorescently labeled. Primary tumor growth, invasion to stromal tissues, as well as bone and lung metastasis will be examined. 2) To determine whether increasing JNK activity in vivo enhances invasion and metastasis, we will test whether overexpression of constitutive JNK in MMTV-Wnt1 transgenic mouse mammary tumors using the novel TVA technology (injection of targeted retrovirus into mammary ducts) can reverse their low metastatic potential. 3) To determine the clinical associations of JNK phosphorylation in human breast cancers. We will use immunohistochemistry to test whether phospho-JNK levels are correlated with status of DCIS, invasion, and metastasis in breast cancer patients. The study will shed light on the role of JNK in breast cancer progression and lay a foundation for future elucidation of the molecular mechanism underlying these JNK functions in cancer metastasis. The study will also open up opportunities for developing new treatments against aggressive and metastatic breast cancer.
The overall objective of this proposal is to explore the role of a signaling protein called JNK in breast cancer metastasis. Since the ability of a tumor to metastasize is the major determinant of cancer patient mortality, defining the molecular pathways critical for tumor metastasis is a high priority in cancer research. A large percentage of patients with early stage breast cancer already have disseminated breast cancer cells in circulation and distant organs by the time primary tumors are surgically removed. Thus, secondary breast tumors and metastatic malignancy can relapse or occur long after surgery. In addition to their high motility, metastatic breast cancer cells show growth advantage over non-metastatic cells both in vitro and in vivo. To prevent and treat metastatic breast cancer accordingly requires blockade of both cancer cell proliferation and spreading. Recently, we found that inhibiting JNK activation blocked proliferation, migration, and invasion of all tested human and mouse breast cancer cell lines in vitro . Based on this and other evidence that JNK may possess several important functions in breast cancer cells, we propose that JNK is an integrator and coordinator for diverse signals involved in breast cancer metastasis. It regulates multiple steps in cancer spreading. Thus, inhibition of JNK may block breast cancer metastasis triggered by various signals, while abnormal JNK activity may lead to a higher invasion and metastasis potential in breast cancer cells. In this study, we will test whether suppressing JNK activity can impede breast cancer metastasis in mouse models. We will also examine whether increasing JNK activity can enhance breast cancer metastasis in mouse models. Finally, we will assess if there is a correlation between activated JNK and stages of breast cancer. The successful accomplishment of this project will lay a solid foundation for future study of the molecular mechanism underlying the JNK function in breast cancer metastasis and pave the way for developing effective new therapeutic strategies targeting JNK.