TAMOXIFEN AND RETINOIC ACID EFFECT ON THE UTERUS

在这十年中，美国有150多万女性 将被新诊断为浸润性乳腺癌，约30% 他们最终会死于这种疾病。乳房的三分之二 癌症出现在绝经后时期。癌 他莫昔芬的预防试验目前正在 女性患乳腺癌的风险很高。到了2000年，它 有可能会有成千上万的女性 他莫昔芬有很长一段时间，我们必须 尽可能多地了解药物的作用机制。 我们研究工作的长期目标是提高 对潜在的分子机制的知识水平 他莫昔芬治疗中常见的子宫滋养作用 了解三苯氧胺治疗与子宫内膜的关系 肿瘤。我们的工作假设是他莫昔芬诱导 子宫内膜的病理改变是由于 控制细胞的基因表达失调 增殖和凋亡。我们将进行详细的分析 他莫昔芬和4-HPR(芬维替尼；a)的分子效应 维甲酸衍生物)对子宫内膜的作用。最新进展 4-羟基喜树碱联合三苯氧胺预防乳腺癌 战略是NCI的优先事项。然而，这种治疗的效果 对子宫的影响还没有明确的确定。我们将确定 化疗药物对肿瘤细胞mRNAs表达的影响 子宫中雌激素调节基因的蛋白质，如 原癌基因和生长因子。此信息应提供 关于他莫昔芬如何以及为什么与子宫内膜相关的线索 肿瘤和IF-4-HPR对子宫滋养功能的调节作用 他莫昔芬。细胞凋亡的失调已被提出 在包括乳腺癌在内的肿瘤发病机制中起重要作用。至 测试我们的假设，即dsys对细胞凋亡的调节是 三苯氧胺相关子宫病变演变中的事件， 我们将确定p53、bcl2和bax的表达是否发生变化 在长期服用他莫昔芬和4-HPR的过程中。这是自相矛盾的 他莫昔芬的雌激素激动剂活性引起的高 与以下因素相关的子宫内膜病理性改变的发生率 他莫昔芬疗法。如果对这种药物的作用机制有更多了解 在子宫细胞中的作用，有可能避免这种不受欢迎的情况 副作用。我们将使用双混合系统来确定 子宫细胞含有特定的蛋白质(S)或辅助激活因子(S)， 介导三苯氧胺激活的转录活性 雌激素受体。这将是我们迈向 了解子宫细胞的转录活性是如何 体内受他莫昔芬刺激。对致病机理的认识 他莫昔芬和4-HPR对子宫上皮细胞的作用 对他莫昔芬作为一种 乳腺癌的化学预防方案。

During this decade, more than 1.5 million women in the United States will be newly diagnosed with invasive breast cancer, and about 30% of them will ultimately die of the disease. Two thirds of the breast cancers are manifested in the post-menopausal period. Cancer prophylaxis trials for tamoxifen are currently underway on groups of women at high risk for developing breast cancer. By the year 2000, it is possible that many hundreds of thousands of women will be taking tamoxifen for a long period of time, and it is imperative that we know as much as possible about the mechanism of action of the drug. The long range goal of our research effort is to raise the basic level of knowledge on the molecular mechanism underlying the uterotrophic effects commonly seen with tamoxifen therapy in order to understand the association between tamoxifen therapy and endometrial neoplasia. Our working hypothesis is that tamoxifen-induced pathological changes in the uterine endometrium are due to dysregulation of expression of the genes which control cell proliferation and apoptosis. We will carry out a detailed analysis of the molecular effects of tamoxifen and 4-HPR (fenretinide; a retinoic acid derivative) on the uterine endometrium. The development of 4-HPR combined with tamoxifen as a breast cancer chemoprevention strategy is a priority at NCI. However, the effect of this treatment on the uterus has not been clearly established. We will determine the effect of these chemotherapeutics on the expression of mRNAs and proteins for estrogen-regulated genes in the uterus, such as protooncogenes and growth factors. This information should provide clues as to how and why tamoxifen is associated with endometrial neoplasia and if 4-HPR can modulate the uterotrophic effect of tamoxifen. Dysregulation of apoptosis has been proposed to contribute to pathogenesis of neoplasms, including breast cancer. To test our hypothesis that dsyregulation of apoptosis is a causative event in the evolution of tamoxifen-associated uterine pathologies, we will determine if expression of p53, bcl-2 and bax is altered during long-term tamoxifen and 4-HPR treatment. It is the paradoxical estrogen agonist activity of tamoxifen that causes the high prevalence of pathological endometrial changes associated with tamoxifen therapy. If more is known about the drug's mechanism of action in uterine cells, it may be possible to avoid this undesirable side effect. We will use the two-hybrid system to determine if uterine cells contain specific protein(s) or co-activator(s) that mediate the transcriptional activity of the tamoxifen-activated estrogen receptor. This will serve as our first step toward understanding how transcriptional activity in uterine cells is stimulated by tamoxifen in vivo. An understanding of the mechanism of action of tamoxifen and 4-HPR on uterine epithelia is of interest and of the utmost relevance to the evaluation of tamoxifen as a chemopreventive regimen for breast cancer.