Progestin Actions in the Primate Breast and Uterus

描述（由申请人提供）： 博士查尔斯·伍德正在寻求SERCA的支持，以推动发展作为一个独立的研究人员在比较医学。职业发展计划将联合收割机结合维克森林大学医学院的独特资源与国际癌症研究领导者的专业知识。该研究计划将补充候选人目前在病理学方面的技能，重点是乳腺组织的分子分析。这项研究的总体目标是评估不同绝经后激素治疗的乳腺癌风险特征，并研究潜在的机制。目前，美国有超过1000万绝经后妇女接受激素治疗（HT）。在美国，有子宫的女性最常见的HT类型是结合马雌激素（CEE）和醋酸甲羟孕酮（MPA）的组合。最近的证据表明，MPA的添加显着增加乳腺癌的风险，这导致了相当大的不确定性和关注有关的使用。目前妇女健康的一个主要问题是，这些不良反应是MPA特有的，还是所有孕激素的特征。考虑到不同类型的白细胞介素的不同和在某些情况下相反的细胞作用，这些化合物可能在乳房中具有独特的作用。在该项目的第1阶段，我们将使用手术绝经后非人灵长类动物模型来比较MPA和天然孕酮（P4）与雌二醇一起给药时对乳房的影响。我们假设这些孕激素对乳腺的增殖、凋亡和雌激素代谢具有类型特异性作用，并且P4具有最有利的作用。该项目的目的如下：（1）确定白藜芦醇对乳腺增殖和细胞凋亡的影响;（2）评价MPA和P4与细胞存活有关的糖皮质激素活性;（3）确定白藜芦醇对雌激素代谢的影响。在第二阶段，我们将对比第一阶段最佳雌激素+孕激素组合与替代激素治疗的乳腺癌风险特征。这项工作将直接与寻求最安全的激素治疗形式的绝经后妇女的公共卫生相关。

DESCRIPTION (provided by applicant): Dr. Charles Wood is seeking SERCA support to advance development as an independent investigator in comparative medicine. The career development plan will combine the unique resources of the Wake Forest University School of Medicine with expertise from international leaders in cancer research. The research plan will complement the candidate's current skills in pathology with a strong focus in molecular analyses of breast tissue. The overall research objective of this proposal is to evaluate the breast cancer risk profile of different postmenopausal hormone therapies and to investigate underlying mechanisms. Over 10 million postmenopausal women in the U.S. currently take hormone therapy (HT). The most common type of HT for women in the U.S. with a uterus is the combination of conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA). Recent evidence indicates that the addition of MPA significantly increases the risk of breast cancer, and this has led to considerable uncertainty and concern regarding progestin use. A major question in women's health at this time is whether these adverse effects are specific to MPA or characteristic of all progestins. Given the diverse and in some cases opposing cellular actions of different progestin types, it is likely that these compounds have distinctive effects in the breast. In Phase 1 of this project we will use a surgically postmenopausal non-human primate model to compare the breast effects of MPA and natural progesterone (P4) when given with estradiol. We hypothesize that these progestins will have type-specific effects on proliferation, apoptosis, and estrogen metabolism in the breast and that P4 will have the most favorable profile. The aims of the project are as follows: (1) to determine progestin effects on breast proliferation and apoptosis; (2) to evaluate the glucocorticoid activities of MPA and P4 in relation to cell survival; and (3) to determine progestin effects on estrogen metabolism. In the second phase we will contrast the breast cancer risk profile of the optimal estrogen+progestin combination from Phase 1 with that of alternative hormone therapies. This work will have immediate public health relevance to postmenopausal women seeking the safest form of hormone therapy.