MITOTIC MODIFIERS OF HORMONE-DEPENDENT BREAST CANCER

乳腺癌是美国女性死亡的主要原因 在过去的十年里，其发病率迅速上升。 这 计划项目的重点是生物机制， 控制细胞增殖，调节基因型和表型 细胞的变化，并影响肿瘤的侵袭和转移。 几个创新的新假设产生于最近的结果在几个 我们的实验室将在拟议的研究中进行测试。 突出 其中一些，我们提出组成型多胺合成可 启动侵袭性肿瘤表型;胰岛素样生长因子 结合蛋白可以调节肿瘤细胞增殖;该变体 孕激素受体可能对孕激素的作用产生负性影响; 嗜中性粒细胞可以在基底膜上产生孔洞， 肿瘤细胞穿透并侵入组织;并且肿瘤细胞可以 在雌激素剥夺后产生增强的雌二醇敏感性。 该方案项目的总体目标是审查机制， 其改变细胞的有丝分裂、细胞增殖和转移行为， 乳腺癌细胞在体外液体培养中生长，在动物体内生长 系统和患者自发。 识别这些 机制应允许针对具体的关键过程进行治疗。 参与本研究的研究者的优势和专业知识 计划项目有助于重点关注几个关键的监管步骤 包括多胺代谢（项目1）、胰岛素样生长因子 及其结合蛋白（项目2），孕酮受体生理学 和受体变体（项目3），控制侵袭性的因素， 转移（项目4）和调节对雌激素的反应性 （项目5）。 实验通过直接的 检查特定的分子过程，通过评估细胞变化， 以及通过检查生物学事件如动物模型中的转移。 全面了解激素对有丝分裂过程的控制， 能够识别过程中被忽略的关键步骤， 向侵袭性肿瘤表型演变。 由此产生的数据 研究应允许选择几个关键的治疗步骤 干预 虽然更完全地阻断芳香化酶是目前的趋势， 作为优先事项，我们希望拟议的研究能够确定其他几个步骤， 如鸟氨酸脱羧酶作为治疗干预的靶点。

Breast cancer is the leading cause of death in women in the United States and its incidence has rapidly increased over the past decade. This Program Project focuses on the biologic mechanisms whereby hormones control cellular proliferation, modulate genotypic and phenotypic cellular changes, and influence tumor invasiveness and metastasis. Several innovative new hypotheses arising from recent results in several of our laboratories will be tested in the studies proposed. To highlight some of these, we propose that constitutive polyamine synthesis may initiate an aggressive tumor phenotype; that insulin-like growth factor binding proteins may modulate tumor cell proliferation; that variant progesterone receptors may exert negative effects on progestin action; that neutrophils may serve to create holes in basement membranes allowing tumor cells to penetrate and invade tissues; and that tumor cells may develop enhanced estradiol sensitivity upon estrogen deprivation. The overall goals of the Program Project are to examine the mechanisms which modify the mitotic, cell proliferative, and metastatic behavior of breast cancer cells growing in vitro in liquid culture, in vivo in animal systems and spontaneously in patients. Identification of these mechanisms should allow targeting of therapy to specific key processes. The strengths and expertise of the investigators participating in this Program Project facilitate focus on several key regulatory steps including polyamine metabolism (Project 1), insulin-like growth factors and their binding proteins (Project 2), progesterone receptor physiology and receptor variants (Project 3), factors controlling invasiveness and metastasis (Project 4), and regulation of responsiveness to estrogens (Project 5). Experiments address testable hypotheses by directly examining specific molecular processes, by evaluating cellular changes, and by examining biologic events such as metastases in animal models. A full understanding of the hormonal control of mitotic processes will enable identification of key steps which are bypassed in the process of evolution to aggressive tumor phenotypes. Data resulting from these studies should allow selection of several key steps for treatment intervention. While more complete blockade of aromatase is a current priority, we expect the proposed studies to identify several other steps, such as ornithine decarboxylase, as targets for therapeutic intervention.