Cancer growth results from uncontrolled cell proliferation, but augmented survival responses in the presence of cellular stress contribute to tumor growth and drug- or radio-resistance. Cells expressing wildtype p53 respond to DNA damage by enhancing p53 expression and stability. C-Jun N-terminal kinase (JNK) activity is also induced by diverse forms of stress, and it enhances p53 activity. In the absence of stress however, basal JNK is important for cell cycle transit. JNK also conveys growth factor receptor or matrix mediated tumor cell survival and migration. We have published that IGF-I (Insulin-like growth factor-I) stimulates JNK in breast cancer cells, while inhibition of basal JNK inhibits cell proliferation by G2/M overexpression. Our preliminary findings with the jnk1(-/-) and jnk2(-/-) mice suggest both lactation and involution defects. Moreover, using the Polyoma Middle T Antigen (PyV MT) mouse model, where mammary tumors and metastases are highly phosphotidylinositol 3 kinase-dependent (PI3K), our preliminary data are indicating that PyV MT/jnk1() and PyV MT/jnk2() mice experience delayed or inhibited mammary tumor development. We hypothesize that JNK1 and JNK2 will perform distinct roles in mammary gland development, tumorigenesis and chemotherapeutic responsiveness. To test this hypothesis, we have established Balb/c mice bearing homozygous deletions of jnk1 or jnk2. We are also generating a mouse that lacks both jnk1 and jnk2 in the mammary gland, thereby allowing us to test for compensation between JNK1 and 2. In this proposal, we will study the biological importance of JNK1 and 2 in both normal mammary gland development and mammary tumorigenesis.
Aim 1 will study the effect of JNK1 and/or 2 loss on normal mammary gland development and function. Part A will investigate the effects of JNK1 or JNK2 in mammary gland development. Part B will employ mice bearing a conditional knockout of JNK1 to investigate the effects of compound JNK1/2(-/-) on mammary gland development.
Aim 2 will study effects of JNK1 and/or JNK2 loss on mammary tumorigenesis, metastases, and therapeutic response. Part A will determine if loss of JNK1 or 2 lengthens mammary tumor latency in a p53(-/-) mouse model. Part B will investigate the role of PI3K and JNK in the PyV MT mediated mammary tumorigenesis, metastases, and response to taxol treatment. These studies will allow us to determine the best fashion to target JNK for therapeutic benefit.
