DNA Replication Licensing and Progenitor Numbers Are Increased by Progesterone in Normal Human Breast
DNA Replication Licensing and Progenitor Numbers Are Increased by Progesterone in Normal Human Breast
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DOI：
10.1210/en.2008-1630
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发表时间：
2009-07-01
期刊：
影响因子：
4.8
通讯作者：
Clarke, Christine L.
中科院分区：
文献类型：
--
作者：
Graham, J. Dinny;Mote, Patricia A.;Clarke, Christine L.
非妊娠期乳腺增生在月经周期的黄体期最高，此时血清孕酮水平较高，并且已知在激素替代治疗中暴露于孕酮类似物会增加乳腺癌风险，但对孕酮在人类乳腺中的增殖作用知之甚少。在正常人乳腺模型中，我们已经表明孕酮通过激活参与DNA复制许可的途径，包括E2 F转录因子、染色质许可和DNA复制因子1（Cdt 1），增加5-溴-2 '-脱氧尿苷的掺入和增加细胞数量，和微小染色体维持蛋白，以及参与动粒形成的蛋白质包括Ras-相关的核蛋白（Ran）和染色体凝聚1（RCC 1）的调节。孕酮增加了能够产生肌上皮细胞和腔上皮细胞的祖细胞，表明孕酮影响上皮细胞谱系分化。因此，我们已经证明，孕酮通过激活DNA复制许可和动粒形成以及增加双能祖细胞数量来增强正常人乳腺细胞的增殖。（内分泌学150：3318-3326，2009）
Proliferation in the nonpregnant human breast is highest in the luteal phase of the menstrual cycle when serum progesterone levels are high, and exposure to progesterone analogues in hormone replacement therapy is known to elevate breast cancer risk, yet the proliferative effects of progesterone in the human breast are poorly understood. In a model of normal human breast, we have shown that progesterone increased incorporation of 5-bromo-2'-deoxyuridine and increased cell numbers by activation of pathways involved in DNA replication licensing, including E2F transcription factors, chromatin licensing and DNA replication factor 1 (Cdt1), and the minichromosome maintenance proteins and by increased expression of proteins involved in kinetochore formation including Ras-related nuclear protein (Ran) and regulation of chromosome condensation 1 (RCC1). Progenitor cells competent to give rise to both myoepithelial and luminal epithelial cells were increased by progesterone, showing that progesterone influences epithelial cell lineage differentiation. Therefore, we have demonstrated that progesterone augments proliferation of normal human breast cells by both activating DNA replication licensing and kinetochore formation and increasing bipotent progenitor numbers. (Endocrinology 150: 3318-3326, 2009)