Significance and mechanisms of relative progesterone receptor isoform expression in normal and malignant target tissues

卵巢激素孕酮在正常女性生理学中具有关键作用，在子宫和卵巢中;在乳腺和大脑中。孕酮通过人孕酮受体发挥其生理作用，人孕酮受体表达为两种受体蛋白（PRB和PRA）。这些是相同的，除了PRA比PRB短，目前的知识支持这两种蛋白质在正常生理学中的作用。PR也在乳腺癌中表达，其作用之一可能是抑制雌激素作用，从而限制肿瘤生长。缺乏PR的肿瘤将缺乏这种能力，这可能与临床预后较差有关。我们已经表明，原发性肿瘤缺乏PR更有可能进展到继发性部位，这可能为这种可能性提供支持。此外，我们已经表明，过度表达的一个PR亚型在乳腺癌中可能是生物学意义的PR缺乏：肿瘤主要表达一个亚型与预后较差的features.This project is aimed at investigating how PRA and PRB explain their effects on the range of孕酮target in normal and malignant tissues.我们将通过确定PR亚型是否位于表达一种PR亚型的细胞与表达两种PR亚型的细胞中的相同核位点来实现这一点，以探索蛋白质是否在靶细胞中单独起作用。然后，我们将询问如果仅表达一种同种型（PRA或PRB）与PRA和PRB两者相比，PR活性是否不同。另一个将被探讨的主要问题是PRA和PRB的相对水平被控制的方式，以及这是否在乳腺癌中被改变。最后，我们将探讨PR亚型表达的临床意义。如果实现了，这个项目的目标将描绘个人和联合行动-这一领域是超过2000字符，文本被删除，以提出申请。原始申请的副本可从存档硬拷贝

The ovarian hormone progesterone has a pivotal role in normal female physiology, in the uterus and ovary; in the mammary gland and in the brain. Human progesterone receptor, through which progesterone exerts its physiological effects, is expressed as two receptor proteins (PRB and PRA). These are identical except that PRA is shorter than PRB and present knowledge supports a role for both proteins in normal physiology. PR is also expressed in breast cancers, where one of its roles may be to inhibit oestrogen action and thereby limit tumour growth. A tumour which lacks PR would lack this capacity and this may be clinically associated with poorer prognosis. We have shown that primary tumours lacking PR are more likely to progress to secondary sites and this may provide support for this possibility. In addition, we have shown that over-expression of one PR isoform in breast cancers can be as biologically significant as lack of PR: tumours expressing predominantly one isoform were associated with poorer prognosis features.This project is aimed at investigating how PRA and PRB exert their effects on the range of progesterone targets in normal and malignant tissues. We will do this by determining whether PR isoforms are located in the same nuclear site in cells expressing one versus cells expressing both PR isoforms, to explore whether the proteins act separately in target cells. We will then ask whether the PR activity is different if only one isoform (PRA or PRB) is expressed versus both PRA and PRB. Another major issue which will be explored is the way in which the relative levels of PRA and PRB are controlled, and whether this is altered in breast cancers. Finally, we will explore the clinical significance of PR isoform expression. If achieved, the aims of this project will delineate the individual and combined action of - THIS FIELD WAS OVER 2000 CHARS, TEXT WAS REMOVED TO LODGE THE APPLICATION. A COPY OF THE ORIGINAL APPLICATION IS AVAILABLE FROM ARCHIVE-HARDCOPY