CHEMOPREVENTION OF BREAST CANCER BY OVARIAN HORMONES

通过卵巢激素化学预防乳腺癌

• 批准号: 2841577
• 负责人: STEVEN M SWANSON
• 金额: $ 9.82万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-07-15 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2841577
• 关键词: apoptosis; breast neoplasms; cancer prevention; carcinogenesis inhibitor; cell cycle; cell differentiation; chemical carcinogen; chemoprevention; dosage; drug administration rate /duration; drug screening /evaluation; estradiol; female; gene expression; hormone regulation /control mechanism; hormone therapy; immunocytochemistry; mammary epithelium; methylnitrosourea; neoplasm /cancer chemotherapy; neoplasm /cancer transplantation; neoplastic transformation; nonhuman therapy evaluation; northern blottings; progesterone

Mothers who bear their first child by their late teens have about half the risk of developing breast cancer relative to nulliparous women. The rat is a good model for studying the role of hormones in breast cancer since, for example, young rats become nearly refractory to mammary carcinogenesis after delivering a litter of pups. Administration of high doses of estradiol and progesterone to rats can yield serum titers of these steroids which approximate their levels reached during pregnancy. When virgin rats are treated with high doses of estradiol and progesterone, they become as refractory to chemically-induced mammary carcinogenesis as parous rats with no apparent toxic effects. Our objective is to understand the mechanism by which high doses of these two hormones protect the mammary gland from developing cancers. Our hypothesis is that treatment with estradiol and progesterone differentiates transformed mammary epithelial cells, thereby preventing them from developing into frank carcinomas. We propose to use morphological, histological, biochemical and molecular methods to study the biology of the carcinogen-exposed mammary gland as a function of estradiol and progesterone treatment. We will also test an alternative hypothesis that these hormones act systemically rather than directly on the mammary epithelial cells. Mammary epithelial cells from hormone treated or control donors will be transplanted into treated or control recipients to determine if the refractory phenotype segregates with treatment of the mammary cells or treatment of the rats in which the cells are transplanted. We also plan a series of studies to determine the minimum dose and length of hormone treatment necessary to confer protection of the mammary gland from carcinogenesis. These studies should provide important information regarding the mechanism by which high levels of estrogen and progesterone protect the mammary gland from carcinogenesis and may help to provide the basis for fixture chemoprevention trials in women.

在十几岁时生下第一个孩子的母亲， 与未生育妇女相比，患乳腺癌的风险更高。大鼠是 研究激素在乳腺癌中的作用的一个很好的模型，因为， 例如，年轻的大鼠几乎对乳腺癌的发生不敏感 在生下一窝幼崽后给予高剂量的 雌激素和孕激素对大鼠的血清滴度可以产生这些 类固醇接近怀孕期间达到的水平。当 用高剂量的雌二醇和孕酮处理未交配的大鼠， 它们变得对化学诱导的乳腺癌形成具有抵抗力， 经产大鼠，无明显毒性作用。我们的目标是了解 高剂量的这两种激素保护 乳腺癌的发展。我们的假设是治疗 与雌二醇和孕酮区分转化乳腺癌 上皮细胞，从而阻止他们发展成弗兰克 癌我们建议使用形态学，组织学，生物化学和 用分子生物学方法研究致癌物暴露的乳腺癌生物学 腺作为功能的雌二醇和孕酮治疗。我们还将 测试另一种假设，即这些激素的作用是系统性的， 而不是直接作用于乳腺上皮细胞。乳腺上皮细胞 将来自激素治疗或对照供体的细胞移植到治疗的 或对照接受者以确定难治性表型是否分离 与治疗乳腺细胞或治疗其中 细胞被移植。我们还计划进行一系列研究，以确定 最低剂量和激素治疗时间， 保护乳腺免受致癌作用。这些研究应 提供关于高级别工作人员 雌激素和孕激素保护乳腺癌的发生 并可能有助于为固定化学预防试验提供基础 妇女