Progestin Actions in the Primate Breast and Uterus

查尔斯·伍德博士正在寻求SERCA的支持，以推动发展作为一个独立的调查员， 比较医学职业发展计划将联合收割机结合维克森林的独特资源 大学医学院，拥有癌症研究领域国际领先者的专业知识。研究 计划将补充候选人目前的病理学技能，重点是分子分析， 乳房组织这项建议的整体研究目的，是评估 不同的绝经后激素治疗，并研究潜在的机制。超过10万 美国绝经后妇女目前采用激素疗法（HT）。最常见的HT类型 在美国，有子宫的妇女是结合马雌激素（CEE）和 醋酸甲羟孕酮（MPA）。最近的证据表明，添加MPA显着 增加了乳腺癌的风险，这导致了相当大的不确定性和关注， 使用维生素A。目前妇女健康的一个主要问题是，这些不良影响是否具有特异性 MPA或所有孕激素的特征。考虑到不同的，在某些情况下相反的细胞行为， 不同类型的乳腺激素，很可能这些化合物在乳房中具有独特的作用。在阶段1中 在这个项目中，我们将使用一个手术绝经后的非人类灵长类动物模型来比较乳房 MPA和天然孕酮（P4）与雌二醇一起给药时的作用。我们假设这些 孕激素对乳腺癌细胞的增殖、凋亡和雌激素代谢具有类型特异性作用。 乳房和P4将具有最有利的轮廓。该项目的目标如下：（1） 检测β-半乳糖苷酶抑制剂对乳腺细胞增殖和凋亡的影响;（2）检测糖皮质激素的活性 MPA和P4与细胞存活的关系;（3）确定孕酮对雌激素代谢的影响。在 第二阶段，我们将对比最佳雌激素+孕激素的乳腺癌风险特征， 与替代性激素疗法相结合。这项工作将立即公开 健康相关性绝经后妇女寻求最安全的激素治疗形式。

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 P4will 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.