NOVEL MECHANISM FOR TAMOXIFEN-INDUCED ENDOMETRIAL ATYPIA

描述（改编自研究者摘要）：他莫昔芬是 最常见的乳腺癌辅助治疗处方，并采取 这个国家和世界各地的妇女每天都在这样做。 的发展 子宫内膜增生、细胞异型性和新发子宫内膜癌 他莫昔芬治疗最严重的副作用。 我们的研究团队有 一直在使用生长在子宫内膜和乳腺癌细胞中的他莫昔芬进行研究 体外，我们的初步研究结果指出了一种新的机制 他莫昔芬会导致细胞损伤。 一种酶，含黄素单加氧酶 5 (FMO5)，将他莫昔芬转化为代谢副产物 tmf*，从而损害 脱氧核糖核酸。 Tmf* 与 DNA 结合并导致称为加合物的结构损伤。 我们的 初步数据表明，FMO5的生产是由 激素黄体酮，反过来又通过黄体酮受体发挥作用。 黄体酮受体以两种形式存在：A 和 B。有趣的是，我们有 结果表明，只有 B 型孕激素受体才能刺激 FMO5的生产。 我们假设发展出非典型的女性 子宫内膜生长或癌症对他莫昔芬的反应之所以如此，是因为它们 子宫内膜细胞含有相对较高水平的 B 型 孕激素受体，在孕激素的影响下，刺激 酶FMO5的产生。 我们的假设步骤是：（1） 黄体酮与黄体酮受体 B 结合 - (2) 产生 FMO5 - (3) 他莫昔芬代谢成反应性副产物 tmf* - (4) Tmf* 结合 DNA 造成结构损伤（加合物） - (5) 发生 DNA 突变 - (6) 在极少数情况下，会发生子宫内膜癌。 我们现在希望测试一下 患者的假设。 使用安全且简单的办公技术，我们有 已经开始对服用他莫昔芬的妇女进行子宫内膜取样。 我们 建议测试子宫内膜样本中是否存在 B 型 黄体酮受体；然后我们将确定 FMO5 和 DNA 是否加合物 表明 DNA 结构损伤增加。 此外，我们将 雌激素受体和其他生长因子的测定 他莫昔芬可能起作用。 我们的长期目标是确定哪些因素最好 与他莫昔芬诱导的子宫内膜的最终出现相关 异常。 通过筛选这些因素，我们希望能够识别出那些 有患子宫内膜癌风险的女性。 一个可靠的 子宫内膜癌筛查测试将使他莫昔芬变得更加安全 为有需要的后代妇女提供药物。

DESCRIPTION (Adapted from the Investigator's Abstract): Tamoxifen is the most common prescribed adjuvant therapy for breast cancer, and is taken daily by women throughout this nation and the world. The development of endometrial hyperplasia, cellular atypia, and new endometrial cancers are the most serious side effects of tamoxifen treatment. Our research team has been studying tamoxifen using endometrial and breast cancer cells grown in vitro, and our preliminary findings point to a novel mechanism by which tamoxifen causes cellular damage. An enzyme, flavin-containing monoxygenase 5 (FMO5), converts tamoxifen into a metabolic by-product tmf* that damages DNA. Tmf* binds to DNA and causes structural damage called adducts. Our preliminary data indicate that the production of FMO5 is controlled by the hormone progesterone, which in turn acts through the progesterone receptor. Progesterone receptors exist in two forms, A and B. Interestingly, we have shown that only the B form of the progesterone receptor stimulates the production of FMO5. We hypothesize that women who develop atypical endometrial growth or cancers in response to tamoxifen do so because their endometrial cells contain relatively high levels of the B form of the progesterone receptor, which under the influence of progesterone, stimulate the production of the enzyme FMO5. The steps in our hypothesis are: (1) Progesterone binds to progesterone receptor B - (2) Production of FMO5 - (3) Tamoxifen is metabolized into a reactive by-product, tmf* - (4) Tmf* binds to DNA causing structural damage (adducts) - (5) DNA mutations occur - (6) In rare cases, endometrial cancer develops. We now wish to test this hypothesis in patients. Using a safe and simple office technique, we have already begun to sample the endometria of women taking tamoxifen. We propose to test the endometrial samples for the presence of the B form of the progesterone receptor; we will then determine if FMO5 and DNA adducts indicative of structural DNA damage are increased. In addition, we will assay for estrogen receptors and other growth factors through which tamoxifen may act. Our long-term goal is to determine which factors best correlate with the eventual appearance of tamoxifen-induced endometrial abnormalities. By screening for these factors, we hope to identify those women who are at risk for developing endometrial cancer. A reliable screening test for endometrial cancer would make tamoxifen an even safer medicine for future generations of women who need it.