The role of JNK in Mammary tumor development

描述（由申请人提供）：癌症生长是由不受控制的细胞增殖引起的，但在细胞应激存在下增强的存活反应有助于肿瘤生长和耐药性或耐放射性。表达野生型p53的细胞通过增强p53表达和稳定性来响应DNA损伤。C-Jun N-末端激酶（JNK）活性也由多种形式的应激诱导，并且其增强p53活性。然而，在没有应激的情况下，基础JNK对于细胞周期转运是重要的。JNK还传递生长因子受体或基质介导的肿瘤细胞存活和迁移。我们已经发表了IGF-I（胰岛素样生长因子-I）刺激乳腺癌细胞中的JNK，而抑制基础JNK通过G2/M过表达抑制细胞增殖。我们对jnk 1（-/-）和jnk 2（-/-）小鼠的初步研究结果表明，哺乳和退化缺陷。此外，使用多瘤中T抗原（PyV MT）小鼠模型，其中乳腺肿瘤和转移是高度磷脂酰肌醇3激酶依赖性的（PI 3 K），我们的初步数据表明PyV MT/jnk 1（）和PyV MT/jnk 2（）小鼠经历延迟或抑制乳腺肿瘤的发展。我们推测JNK 1和JNK 2在乳腺发育、肿瘤发生和化疗反应中发挥不同的作用。为了检验这一假设，我们建立了Balb/c小鼠轴承纯合缺失jnk 1或jnk 2。我们也正在培育一只在乳腺中同时缺乏JNK 1和JNK 2的小鼠，从而使我们能够测试JNK 1和JNK 2之间的补偿。在本提案中，我们将研究JNK 1和2在正常乳腺发育和乳腺肿瘤发生中的生物学重要性。目的1研究JNK 1和/或2缺失对正常乳腺发育和功能的影响。第一部分将研究JNK 1或JNK 2在乳腺发育中的作用。部分B将使用携带JNK 1条件性敲除的小鼠来研究化合物JNK 1/2（-/-）对乳腺发育的影响。目的2将研究JNK 1和/或JNK 2缺失对乳腺肿瘤发生、转移和治疗反应的影响。A部分将确定JNK 1或2的缺失是否延长p53（-/-）小鼠模型中的乳腺肿瘤潜伏期。部分B将研究PI 3 K和JNK在PyV MT介导的乳腺肿瘤发生、转移和对紫杉醇治疗的反应中的作用。这些研究将使我们能够确定靶向JNK的最佳方式以获得治疗益处。

DESCRIPTION (provided by applicant): 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.