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

卵巢激素黄体酮在正常的女性生理、子宫和卵巢、乳腺和大脑中起着关键作用。人孕酮受体是孕酮发挥生理作用的两种受体蛋白(PRB和PRA)。这些都是相同的，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的作用，从而限制肿瘤的生长。缺乏PR的肿瘤将缺乏这种能力，这可能与临床上预后较差有关。我们已经证明，缺乏PR的原发肿瘤更有可能进展到继发部位，这可能为这种可能性提供支持。此外，我们还发现，在乳腺癌中，一种PR亚型的过度表达与缺乏PR一样具有生物学意义：主要表达一种异构体的肿瘤与较差的预后特征有关。本项目旨在研究PRA和PRB如何在正常和恶性组织中对孕激素靶标范围产生影响。我们将通过确定PR亚型是否位于表达一种PR亚型的细胞和表达两种PR亚型的细胞中的同一核位置来实现这一点，以探索这两种蛋白质是否在靶细胞中单独发挥作用。然后我们会问，如果只表达一种异构体(PRA或PRB)与同时表达PRA和PRB，PR的活性是否不同。另一个将被探索的主要问题是如何控制PRA和PRB的相对水平，以及这一点在乳腺癌中是否会改变。最后，我们将探讨PR亚型表达的临床意义。如果实现，这个项目的目标将勾勒出个人和联合行动-此字段超过2000个字符，文本被删除的申请。原始应用程序的副本可从存档中获得-HARDCOPY

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