Molecular profiles of progesterone receptor loss in human breast tumors
Molecular profiles of progesterone receptor loss in human breast tumors
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DOI：
10.1007/s10549-008-0017-2
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发表时间：
2009-03-01
影响因子：
3.8
通讯作者：
Schiff, Rachel
中科院分区：
文献类型：
--
作者：
Creighton, Chad J.;Osborne, C. Kent;Schiff, Rachel
背景乳腺癌患者的预后和对内分泌治疗的反应与雌激素受体(ER)和孕激素受体(PR)的蛋白表达有关，ER+/PR-患者的预后比ER+/PR+肿瘤患者差。方法为了更好地了解ER+/PR-肿瘤的生物学基础，我们检测了先前发表的5项具有临床指定激素受体状态(ER+/PR+、ER+/PR-和ER-/PR-)的乳腺癌的RNA表达(n>；1000个肿瘤)和DNA拷贝数分布。结果与ER-/PR-和ER-/PR-相比，我们在ER+/PR+中发现了RNA水平升高或降低的基因表达“特征”。我们同样发现了ER-/PR-肿瘤特有的基因特征。另一方面，ER+/PR-肿瘤是三种不同亚型的混合体：表现ER+/PR+特征的肿瘤，表现ER-/PR-特征的肿瘤，以及不与ER+/PR+或ER-/PR-肿瘤相关的肿瘤(我们认为这是“真正的”ER+/PR-)。在对接受他莫昔芬治疗和未接受治疗的患者的分析中，通过RNA图谱定义的ER+/PR-乳腺癌与较差的患者预后相关，比那些纯ER+/PR+模式的患者更差；当使用临床分析来分配ER和PR状态时，这些差异没有观察到。ER+/PR-肿瘤的DNA拷贝数增加或丢失也是ER+/PR+和ER-PR-肿瘤的两倍。与ER+/PR+肿瘤相比，包括PI3K/Akt/mTOR在内的特定致癌途径转录上调的靶点均在ER+/PR-和ER-/PR-中丰富。结论根据RNA图谱的定义，ER+/PR-肿瘤是乳腺癌中一个独特的亚型，具有侵袭性和不良预后，尽管临床上ER+。可以想象，从我们的基因签名衍生的多基因分析可以提供一种改进的临床分析方法，用于推断PR状态，以预测预后和治疗目的。
Background Patient prognosis and response to endocrine therapy in breast cancer correlate with protein expression of both estrogen receptor (ER) and progesterone receptor (PR), with poorer outcome in patients with ER+/PR-compared to ER+/PR+ tumors. Methods To better understand the underlying biology of ER+/PR-tumors, we examined RNA expression (n > 1000 tumors) and DNA copy number profiles from five previously published studies of human breast cancers with clinically assigned hormone receptor status (ER+/PR+, ER+/PR-, and ER-/PR-). Results We identified an expression "signature'' of genes with either elevated or diminished RNA levels specifically in ER+/PR+ compared to ER-/PR- and ER+/PR- tumors. We similarly identified a gene signature specific to ER-/PR - tumors. ER+/PR-tumors, on the other hand, were a mixture of three different subtypes: tumors manifesting the ER+/PR+ signature, tumors manifesting the ER-/PR-signature, and tumors not associating with ER+/PR+ or ER-/PR-tumors (which we considered "true'' ER+/PR-). In analyses of both tamoxifen-treated and untreated patients, ER+/PR-breast cancers defined by RNA profiling were associated with poor patient outcome, worse than those with pure ER+/PR+ patterns; these differences were not observed when using clinical assays to assign ER and PR status. ER+/PR-tumors also showed twice as many DNA copy number gains or losses compared to ER+/PR+ and ER-PR-tumors. Targets of transcriptional up-regulation by specific oncogenic pathways, including PI3 K/Akt/mTOR, were enriched in both ER+/PR- and ER-/PR-compared to ER+/PR+ tumors.Conclusion ER+/PR-tumors as defined by RNA profiling represent a distinct subset of breast cancer with aggressive features and poor outcome, despite being clinically ER+. Multigene assays derived from our gene signatures could conceivably provide an improved clinical assay for inferring PR status for prognostic and therapeutic purposes.