MOLECULAR ANALYSIS OF STAT IN BREAST CANCER CELL

生长因子及其受体的异常作用是 正常人不受控制的增殖和进化的决定因素 乳腺上皮到癌细胞。许多临床、细胞和分子方面的 生物学研究表明，表皮的异常表达 生长因子(EGF)、转化生长因子α(TGFα)和 它们的共同受体(EGFR或相关受体erbB2/neu和erbB3) 常与乳腺细胞的恶性转化有关。 傅博士和其他人最近证明了EGF可以诱导快速 酪氨酸磷酸化与转录因子的核转位 P9l(p9l或STAT1pha)。通过其SH2结构域，p9l直接相互作用 与EGFR结合，并以配体依赖的方式激活。激活的p9l 移位到细胞核并刺激特异性转录 癌基因c-fos的体内外研究。这些研究表明，EGF可以 使用直接信号通路控制核转录事件 (Fu和Zhang，1993)。最近，来自其他实验室的研究已经 表明表皮生长因子、血小板衍生生长因子、脑脊液-L、IL-3、IL-5、IL-6和IL-10均可用于 控制核转录事件的类似直接途径 (Darnell等人，1994年审查)。 乳腺癌研究中的一个基本问题是这是否以及如何 直接信号通路参与了细胞的异常生长和 乳腺细胞的转化。我最近的结果表明，p9l 似乎在乳房癌基因表达的信号转导中非常重要 癌细胞，尤其是那些过度表达EGFR的细胞。更深一层的 对这些信号事件的作用的理解最终可能会提示 治疗乳腺癌的基础。这笔奖学金将允许我 为了进一步研究这种直接信号通路在乳房中的作用 癌细胞，尤其是对自分泌和/或旁分泌的反应- EGF等代理生长因子。

The aberrant action of growth factors and their receptors is one of major determinants in the uncontrolled proliferation and evolution of normal breast epithelium to cancer cells. Many clinical, cellular, and molecular biology studies have indicated that abnormal expression of epidermal growth factor (EGF), transforming growth factor alpha (TGFalpha), and their shared receptor (EGFR or the related receptors erbB2/neu and erbB3) is frequently associated with malignant transformation of breast cells. Dr. Fu and others have recently demonstrated that EGF can induce rapid tyrosine phosphorylation and nuclear translocation of transcription factor p9l (p9l, or STAT1alpha). Through its SH2 domain, p9l directly interacts with EGFR and is activated in a ligand-dependent manner. Activated p9l translocates to the nucleus and stimulates specific transcription of the oncogene c-fos in vitro and in vivo. These studies suggest that EGF can use a direct signaling pathway to control nuclear transcriptional events (Fu and Zhang, 1993). Recently, studies from other laboratories have demonstrated that EGF, PDGF, CSF-l, IL-3, IL-5, IL-6, and IL-1O all use the similar direct pathway in controlling nuclear transcriptional events (reviewed by Darnell et al., 1994). A fundamental question in breast cancer research is whether and how this direct signaling pathway is involved in abnormal cell growth and transformation of breast cells. My recent results have shown that p9l seems to be very important in signaling oncogene expression in breast cancer cells, especially those cells which over-express EGFR. A deeper understanding of the role of these signaling events may eventually suggest a basis for the treatment of breast cancer. This fellowship will allow me to further investigate the role of this direct signaling pathway in breast cancer cells, especially, in response to an autocrine- and/or paracrine- acting growth factor such as EGF.