Mote P A, Graham J D, Clarke C L
Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead Hospital, Darcy Rd, 2145 Westmead, Australia.
Ernst Schering Found Symp Proc. 2007(1):77-107.
Progesterone is an essential regulator of normal female reproductive function, yet recent studies on the use of progestins in hormone replacement therapy have clearly implicated progestins in breast cancer development, a disease initiated early in life at a time of frequent exposure to cycling ovarian hormones. The effects of progesterone are mediated by two distinct nuclear receptor proteins, PRA and PRB. In normal breast PRA and PRB are co-expressed at similar levels in luminal epithelial cells, suggesting that both proteins are required to mediate physiologically relevant progesterone signalling. However, early in breast carcinogenesis PRA:PRB expression is disrupted, resulting in frequent predominance of one isoform. Unbalanced expression of PRA and PRB results in altered hormonal response and aberrant targeting of genes that are not normally progestin-regulated, principally those involved in morphological changes and disruptions of the actin cytoskeleton, and in migration. Movement of PR into discrete nuclear domains, or foci, is a critical step in normal PR transcriptional activity that appears to be aberrant in cancers and likely related to alterations in nuclear morphology, gene expression and cell function associated with tumour cells. Given that exogenous progestins are consumed by millions of women worldwide in the form of hormone replacement therapy and oral contraceptives, it is vital to better understand the mechanisms of progesterone action in the breast.
孕酮是正常女性生殖功能的重要调节因子，但近期有关孕激素在激素替代疗法中应用的研究已明确表明，孕激素与乳腺癌的发生有关。乳腺癌是一种在生命早期、频繁暴露于周期性卵巢激素时就开始的疾病。孕酮的作用由两种不同的核受体蛋白PRA和PRB介导。在正常乳腺中，PRA和PRB在腔上皮细胞中以相似水平共表达，这表明两种蛋白都需要介导生理相关的孕酮信号传导。然而，在乳腺癌发生早期，PRA:PRB的表达被破坏，导致一种异构体频繁占主导。PRA和PRB的不平衡表达导致激素反应改变以及对正常情况下不受孕激素调节的基因的异常靶向，主要是那些参与形态变化、肌动蛋白细胞骨架破坏和迁移的基因。PR进入离散的核区域或核灶是正常PR转录活性的关键步骤，这在癌症中似乎是异常的，并且可能与肿瘤细胞相关的核形态、基因表达和细胞功能的改变有关。鉴于全球数百万女性以激素替代疗法和口服避孕药的形式使用外源性孕激素，更好地了解孕酮在乳腺中的作用机制至关重要。
