Graham J Dinny, Yager Melissa L, Hill Hazel D, Byth Karen, O'Neill Geraldine M, Clarke Christine L
Westmead Institute for Cancer Research, University of Sydney Westmead Hospital, Westmead Millennium Institute, Darcy Road, Westmead, New South Wales 2145, Australia.
Mol Endocrinol. 2005 Nov;19(11):2713-35. doi: 10.1210/me.2005-0126. Epub 2005 Jun 23.
The ovarian hormone progesterone is essential for normal breast development and function. However, it is also implicated in breast cancer development. Progesterone signals through two nuclear receptors [progesterone receptor A (PRA) and progesterone receptor B (PRB)], which display striking differences in transcriptional activity when analyzed separately. The two species are coexpressed equally in normal breast, but expression becomes markedly disrupted in breast cancer, where a predominance of PRA is common. To determine the impact on PR transcriptional activity of the shift from coexpression of PRA and PRB, observed in normal cells, to predominance of PRA, common in cancers, we modeled these changes in PR expression patterns using an inducible model of PRA predominance. At short treatment times progestin regulation was directed toward transcriptional modulators, whereas longer exposure more frequently targeted genes associated with regulation of cell shape, adhesion, and metabolism, and a number of these targets acquired responsiveness only when PRA predominance was achieved. Consistent with this, overexpression of PRA altered progestin effects on cell-substrate attachment and focal adhesion signaling. Our data suggest that disrupted balance of PRA and PRB remodels progestin responsiveness and that altered regulation of morphology and adhesion are important components of altered progestin response in breast cancer.
卵巢激素孕酮对于正常乳腺发育和功能至关重要。然而，它也与乳腺癌的发生有关。孕酮通过两种核受体[孕酮受体A（PRA）和孕酮受体B（PRB）]发挥信号作用，单独分析时，这两种受体在转录活性上表现出显著差异。这两种受体在正常乳腺中同等程度地共表达，但在乳腺癌中表达明显紊乱，其中PRA占优势的情况很常见。为了确定从正常细胞中观察到的PRA和PRB共表达转变为癌症中常见的PRA占优势对PR转录活性的影响，我们使用PRA占优势的诱导模型模拟了PR表达模式的这些变化。在短时间处理时，孕激素调节作用于转录调节因子，而较长时间的暴露更频繁地靶向与细胞形状、黏附及代谢调节相关的基因，并且其中许多靶点仅在PRA占优势时才获得反应性。与此一致的是，PRA的过表达改变了孕激素对细胞与底物附着及黏着斑信号传导的影响。我们的数据表明，PRA和PRB平衡的破坏重塑了孕激素反应性，形态和黏附调节的改变是乳腺癌中孕激素反应改变的重要组成部分。
