TAMOXIFEN AND RETINOIC ACID EFFECT ON THE UTERUS

在这十年中，美国有150多万妇女 将被新诊断为浸润性乳腺癌，约30%的 他们最终会死于疾病。乳房的三分之二 癌症在绝经后时期表现出来。 癌 他莫昔芬的预防试验目前正在进行中， 患乳腺癌的高危女性。到2000年， 可能会有成千上万的女性 他莫昔芬很长一段时间，我们必须 尽可能多地了解药物的作用机制。 我们研究工作的长远目标是提高 在分子机制方面的知识水平 他莫昔芬治疗常见的子宫增重作用， 了解他莫昔芬治疗与子宫内膜异位症之间的关系 肿瘤形成我们的假设是他莫昔芬诱导的 子宫内膜的病理变化是由于 控制细胞的基因表达失调 增殖和凋亡。 我们将进行详细分析 他莫昔芬和4-HPR（芬维A胺; 视黄酸衍生物）对子宫内膜的作用。发展 4-HPR联合他莫昔芬作为乳腺癌的化学预防 战略是NCI的优先事项。然而，这种治疗的效果 对子宫的影响还不清楚康贝特人将以 这些化疗剂对mRNA表达的影响， 子宫内雌激素调节基因的蛋白质，如 原癌基因和生长因子。这些信息应提供 关于他莫昔芬如何和为什么与子宫内膜癌相关的线索 如果4-HPR可以调节子宫的营养作用， 他莫昔芬。 已经提出细胞凋亡的失调 有助于肿瘤的发病机制，包括乳腺癌。到 验证我们的假设，即细胞凋亡的失调是导致 他莫昔芬相关子宫病理学演变中的事件， 我们将确定p53、bcl-2和bax的表达是否改变， 在长期他莫昔芬和4-HPR治疗期间。这是自相矛盾的 他莫昔芬的雌激素激动剂活性， 子宫内膜病理性变化的患病率 他莫昔芬疗法如果更多地了解药物的作用机制， 在子宫细胞中的作用，它可能会避免这种不可取的 副作用我们将使用双混合动力系统来确定是否 子宫细胞含有特定的蛋白质或共激活剂， 介导他莫昔芬激活的 雌激素受体这将是我们 了解子宫细胞中的转录活性 在体内被他莫昔芬刺激。了解其机制， 他莫昔芬和4-HPR对子宫上皮细胞的作用是令人感兴趣的， 与他莫昔芬作为一种 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.