Impact of progesterone receptor subnuclear localisation on progesterone action in endocrine target cells

乳腺癌每年影响1万名澳大利亚妇女，是癌症死亡的主要原因。由女性卵巢产生的激素黄体酮，在女性正常乳房发育的某些方面起着重要作用，也与乳腺癌和子宫内膜癌的发展和反应有关。在正常细胞中，黄体酮通过细胞核中的特定蛋白质（或受体）起作用，我们已经证明，当这种蛋白质活跃时，它会积聚成灶。我们注意到，在癌症中，这种积累被破坏了，这对癌症来说是一个不好的信号。随着乳腺癌的发展，它会导致乳房细胞结构发生许多戏剧性的变化，尤其是在细胞核中，细胞核携带着控制癌细胞行为的遗传信息。细胞核通常被高度组织成不同的区室，这些区室执行细胞的不同功能，如DNA的复制，DNA损伤后的修复，以及对细胞功能重要的特定基因的开启和关闭。这种组织在癌细胞中发生了巨大的变化，似乎这种改变的组织导致了功能的改变。在这个项目中，我们的目标是弄清楚是什么使孕酮受体形成病灶，这些病灶如何参与孕酮的作用，以及细胞核结构的变化如何改变这一过程。这个项目将把细胞核的结构与黄体酮打开或关闭特定基因的能力联系起来，这将提供第一个路标，说明癌细胞细胞核的变化是如何反映在激素信号的变化中。健康妇女在口服避孕药和激素替代疗法中经常接触黄体酮。由于暴露于黄体酮而增加了患乳腺癌的风险，因此有必要了解黄体酮是如何产生异常影响的。这个项目将解决这一重要的健康问题。

Breast cancer affects 10,000 Australian women annually and is a major cause of cancer death. The hormone progesterone, which is produced by the ovaries in women, is responsible for some aspects of the development of the normal breast in women and is also implicated in the development and response of breast and endometrial cancers. In normal cells progesterone acts via a specific protein (or receptor) in the nucleus, and we have shown that this protein accumulates into foci when it is active. We have noticed that in cancers, this accumulation is disrupted, and this is a bad sign for the cancer. As breast cancer develops, it causes many dramatic changes in the structure of cells of the breast, and particularly in the nucleus, which carries the genetic information that programs cancer cell behaviour. The nucleus normally is highly organised into compartments, which carry out different functions of the cell, such as duplication of the DNA, repair of DNA after damage, and switching on and off of particular genes important to the function of the cell. This organisation is altered dramatically in cancer cells, and it seems that this altered organisation is responsible for altered function. In this project we aim to work out what makes the receptor for progesterone form foci, how these foci are involved in the action of progesterone, and how the changed structure of the nucleus changes this process. This project will link the structure of the cell nucleus with the ability of progesterone to switch on or off particular genes, and this will provide the first signposts of how changes seen in cancer cell nuclei are reflected in changed hormonal signalling. Healthy women are regularly exposed to progestins in oral contraceptives and hormone replacement therapy. The known increased risk of breast cancer as a result of exposure to progestins creates an imperative to understand how progesterone may have aberrant effects. This project will address this important health issue.