正常和恶性乳腺中黄体酮受体同种异构体。

P A Mote, J D Graham, C L Clarke
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摘要

黄体酮是正常女性生殖功能的重要调节因子,但最近关于黄体酮在激素替代疗法中的应用的研究清楚地表明,黄体酮与乳腺癌的发展有关,乳腺癌是一种在生命早期因频繁暴露于卵巢激素循环而引发的疾病。黄体酮的作用是由两种不同的核受体蛋白介导的,PRA和PRB。在正常乳腺中,PRA和PRB在腔上皮细胞中以相似的水平共表达,表明这两种蛋白都需要介导生理相关的黄体酮信号传导。然而,在乳腺癌发生的早期,PRA:PRB的表达被破坏,导致一种异构体经常占优势。PRA和PRB的不平衡表达导致激素反应的改变和不受孕激素调节的基因的异常靶向,主要是那些参与形态改变和肌动蛋白细胞骨架破坏以及迁移的基因。PR进入离散核结构域或病灶是正常PR转录活性的关键步骤,在癌症中似乎是异常的,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。鉴于全球数以百万计的妇女以激素替代疗法和口服避孕药的形式服用外源性孕激素,因此更好地了解孕激素在乳房中的作用机制至关重要。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Progesterone receptor isoforms in normal and malignant breast.

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.

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