Identification of a clinically relevant androgen-dependent gene signature in prostate cancer.
Identification of a clinically relevant androgen-dependent gene signature in prostate cancer.
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DOI：
10.1158/0008-5472.can-10-2512
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发表时间：
2011-03-01
期刊：
影响因子：
11.2
通讯作者：
Tindall DJ
中科院分区：
文献类型：
--
作者：
Heemers HV;Schmidt LJ;Sun Z;Regan KM;Anderson SK;Duncan K;Wang D;Liu S;Ballman KV;Tindall DJ
雄激素受体（AR）是治疗非器官局限性前列腺癌（PCa）的主要靶点。针对AR配体结合域的雄激素剥夺疗法（ADTs）不能完全抑制雄激素依赖性信号传导，这对PCa的进展至关重要。因此，需要能够指导开发更有效的adt的信息。系统和生物信息学方法表明，AR调节效应基因表达的机制存在相当大的差异，指出次级转录因子的作用。微阵列和芯片分析的结合使我们确定了依赖AR和转录因子SRF的158个基因特征，占雄激素依赖基因的6%以下。这种AR-SRF特征足以区分微解剖的良性和恶性前列腺样本，它与侵袭性疾病的存在和不良预后相关。与其他类似大小的AR靶基因特征相比，本文描述的AR- srf特征与生化失败的相关性更强。此外，与其他特征相比，它在恶性前列腺组织和良性前列腺组织中富集。据我们所知，这一研究首次证明了雄激素作用与前列腺癌临床相关的独特机制，为开发新的、更有效的ADT形式提供了可能的理论依据。
The androgen receptor (AR) is the principal target for treatment of non-organ confined prostate cancer (PCa). Androgen deprivation therapies (ADTs) directed against the AR ligand-binding domain do not fully inhibit androgen-dependent signaling critical for PCa progression. Thus, information that could direct the development of more effective ADTs are desired. Systems and bioinformatics approaches suggest that considerable variation exists in the mechanisms by which AR regulates expression of effector genes, pointing to a role for secondary transcription factors. A combination of microarray and in silico analyses led us to identify a 158 gene signature that relies on AR along with the transcription factor SRF, representing < 6% of androgen-dependent genes. This AR-SRF signature is sufficient to distinguish microdissected benign and malignant prostate samples, and it correlates with the presence of aggressive disease and poor outcome. Compared to other AR target gene signatures of similar size, the AR-SRF signature described here associates more strongly with biochemical failure. Further, it is enriched in malignant versus benign prostate tissues, compared to other signatures. To our knowledge, this profile represents the first demonstration of a distinct mechanism of androgen action with clinical relevance in PCa, offering a possible rationale to develop novel and more effective forms of ADT.