MITOGEN ACTIVATED PROTEIN KINASES AND BREAST CANCER

乳腺癌的病因和发病机制尚不清楚，但一些观察结果表明，有丝分裂原活化蛋白（MAP）激酶级联在乳腺癌进展中的作用。 我们研究的目的是了解乳腺癌细胞生长和增强侵袭周围组织的机制，这是恶性肿瘤的特征。 先前表明，在乳腺癌中，导致酪氨酸磷酸化的大多数生长和致癌信号激活MAPK级联。活化的MAPK（ERK 1和ERK 2）从细胞质易位到细胞核，在细胞核中它调节核蛋白和转录因子如AP-1，AP-1调节蛋白酶如尿激酶（uPA）和基质金属蛋白酶（MMP-9），这些蛋白酶显示参与基质降解。 我们使用乳腺癌细胞的初步研究表明，MAPK活性的下调破坏细胞增殖，运动和侵袭表型，这表明MAPK级联的激活可能是正常细胞事件和致癌转化的一部分。这一建议是基于这样的假设，即乳腺上皮细胞中MAPK的过表达和/或持续激活导致蛋白酶诱导和细胞运动性增加，导致乳腺和其他肿瘤中侵袭性表型的获得。 本研究的目的有三：（1）研究MAPK（ERK 1）过表达和/或激活对乳腺上皮细胞转化的影响。(2)探讨活化的丝裂原活化蛋白激酶（MAPK）在肿瘤发生和转移中的作用。 (3)探讨MAPK在转基因小鼠乳腺良性增生和恶性病变中的作用。 这些研究将为乳腺癌的发生和发展机制提供重要的新信息。 长期目标是鉴定肿瘤进展的潜在分子事件，这些分子事件是开发合理治疗剂的潜在靶点。

Breast cancer etiology and pathogenesis remain unclear, but several observations suggest a role for the mitogen activated protein (MAP) kinase cascade in breast cancer progression. The aim of our study is to understand the mechanism by which breast cancer cells grow and enhance invasion into surrounding tissues a characteristic feature of malignant tumors. It was previously shown that in breast cancer, most growth and oncogenic signals that leads to tyrosine phosphorylation activates MAPK cascade. The activated MAPK (ERK1 and ERK2) translocates from cytoplasm to the nucleus where it regulates nuclear proteins and transcriptional factors such as AP-1 which regulate proteases such as urokinase (uPA) and matrix metalloproteinase (MMP-9) that are shown to be involved in matrix degradation. Our preliminary studies using breast cancer cells suggest that down regulation of MAPK activity disrupt cell proliferation, motility and invasion phenotype, suggesting that activation of MAPK cascade, might be part of both normal cellular events and oncogenic transformation. This proposal is based on the hypothesis that overexpression and/or consistent activation of MAPK in breast epithelial cells results in increased protease induction and cell motility, leading to the acquisition of an invasive phenotype in breast and other tumor. We have three objectives: (1) To study the effect of MAPK (ERK1) overexpression and/or activation on cell transformation in breast epithelial cells. (2) To study the role of activated MAPK in the induction of tumorigenicity and metastasis. (3) To determine the importance of the MAPK in the induction of benign proliferative and malignant changes in mammary gland using transgenic mice. These studies will provide important new information on the mechanism of breast cancer development and progression. The long term goal is the identification of molecular events underlying tumor progression that are potential targets for the development of rational therapeutic agents.