Expression profiling of human breast cancers and gene regulation by progesterone receptors
Expression profiling of human breast cancers and gene regulation by progesterone receptors
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DOI：
10.1023/b:jomg.0000010028.48159.84
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发表时间：
2003-07-01
影响因子：
2.5
通讯作者：
Horwitz, KB
中科院分区：
文献类型：
--
作者：
Jacobsen, BM;Richer, JK;Horwitz, KB
即使是对乳腺癌的首次表达谱研究也产生了新的见解。例如，有关肿瘤侵袭性、预后、转移潜力或治疗结果的信息编码于原发肿瘤中，并且可以从原发肿瘤中推断出来。另一方面，尚无临床基因组阵列数据发表，涉及乳腺肿瘤发生、肿瘤进展或治疗的激素方面。相反，研究集中在实验模型系统上。我们回顾了目前在临床乳腺癌中发表的阵列分析数据，然后描述了我们在乳腺癌细胞系和异种移植模型中处理孕激素受体（pr）和孕激素作用的研究。我们证明，PR- a和PR- b这两种PR同工异构体在与黄体酮配体时具有大多数不重叠的分子特征，其中PR- b更活跃。此外，我们记录了令人惊讶的发现，无配体pr可以调节基因转录，PR-A更活跃的形式。在切除卵巢的小鼠中，补充雌二醇但缺乏可测量的黄体酮，表达pr - b的肿瘤生长到表达pr - a的肿瘤的两倍大。我们得出结论，在乳腺癌中，pr不仅仅是雌激素受体功能的简单标记。相反，即使在没有配体的情况下，pr的存在和两种同种异构体的比例也直接影响肿瘤表型。
Even the first expression profiling studies of breast cancers have generated new insights. They suggest for example, that information about tumor aggressiveness, prognosis, metastatic potential, or treatment outcome is encoded in, and can be deduced from, the primary tumor. On the other hand no clinical genomic array data have yet been published that deal with hormonal aspects of breast tumorigenesis, tumor progression, or therapeutics. Rather, studies have focused on experimental model systems. We review below the currently published data on array profiling in clinical breast cancer, then describe our studies in breast cancer cell lines and xenograft models dealing with progesterone receptors ( PRs) and the role of progesterone. We demonstrate that the two PR isoforms, PR-A and PR-B, have mostly nonoverlapping molecular signatures when liganded by progesterone, with PR-B the more active form. Additionally, we document the surprising finding that unliganded PRs can regulate gene transcription, with PR-A the more active form. In ovariectomized mice supplemented with estradiol but lacking measurable progesterone, PR-B-expressing tumors grow to twice the size of PR-A-expressing ones. We conclude that in breast cancers, PRs are more than simple markers of estrogen receptor function. Rather, presence of PRs and the ratio of the two isoforms directly influence tumor phenotype, even in the absence of ligand.