ESTROGEN REGULATION OF BREAST CANCER CELL PROLIFERATION

描述：本研究的长期目标是了解 雌激素和抗雌激素调节人乳腺癌细胞增殖， 一开始需要雌激素的细胞如何最终增殖 变得不依赖雌激素和抗雌激素。 实现这些 目标是至关重要的，因为雌激素的独立性的发展， 抗雌激素抵抗是乳腺癌治疗失败的主要原因 癌症患者。 将采取的一种方法是比较 细胞内细胞周期蛋白/CDK途径控制细胞增殖， 雌激素非依赖性乳腺癌细胞系MCF-7 和MCF-7的抗雌激素抗性衍生物，以及一组其他ER+ 和ER-乳腺癌细胞系。 此外，还将进行实验， 以确定干扰细胞周期蛋白/CDK通路是否可以直接 将MCF-7细胞转化为雌激素非依赖性和/或雌激素抗性。 在 目的一、比较细胞周期蛋白激酶（CDK）活性和蛋白水平的调节， 上述细胞系。 在目的II-IV中，细胞周期蛋白/CDK途径将 以多种方式被破坏，包括抑制细胞周期蛋白/CDK 活性、RB功能抑制和细胞周期蛋白基因过表达，以及 这些扰动对fMCF-7细胞激素依赖性的影响 将被审查。 这些研究将确定雌激素的重要靶点 和抗雌激素作用，并提出可能的机制，乳腺癌 肿瘤可以变得雌激素非依赖性和抗雌激素抗性。

DESCRIPTION: The long term goals of this research are to understand how estrogen and antiestrogens regulate human breast cancer cell proliferation, an how cells that initially require estrogen to proliferate eventually become estrogen independent and antiestrogen resistant. Attaining these goals is critical, since the development of estrogen independence and antiestrogen resistance is a major cause of treatment failure in breast cancer patients. On approach that will be taken is to compare regulation of the intracellular cyclin/CDK pathway that controls cell proliferation in the estrogen dependent breast cancer cell line MCF-7, in estrogen independent and antiestrogen resistant derivatives of MCF-7, and in a panel of other ER+ and ER- breast cancer cell lines. In addition, experiments will be carried out to determine whether perturbing the cyclin/CDK pathway can directly convert MCF-7 cells to estrogen independence and/or estrogen resistance. In Aim I, the regulation of protein levels and CDK activity will be compared in the cell lines described above. In Aims II-IV, the cyclin/CDK pathway will be disrupted in a variety of ways including inhibition of cyclin/CDK activity, inhibition of RB function, and overexpression of cyclin genes, and the effects of these perturbations on hormone dependence of fMCF-7 cells will be examined. These studies will identify important targets of estrogen and antiestrogen action, and suggest possible mechanisms by which breast tumors can become estrogen independent and antiestrogen resistant.