Genomic analysis of estrogen cascade reveals histone variant H2A.Z associated with breast cancer progression.
Genomic analysis of estrogen cascade reveals histone variant H2A.Z associated with breast cancer progression.
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DOI：
10.1038/msb.2008.25
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发表时间：
2008
影响因子：
9.9
通讯作者：
White, Kevin P.
中科院分区：
文献类型：
--
作者：
Hua, Sujun;Kallen, Caleb B.;Dhar, Ruby;Baquero, Maria T.;Mason, Christopher E.;Russell, Beth A.;Shah, Parantu K.;Liu, Jiang;Khramtsov, Andrey;Tretiakova, Maria S.;Krausz, Thomas N.;Olopade, Olufunmilayo I.;Rimm, David L.;White, Kevin P.
我们展示了一种研究乳腺癌进展中涉及的转录调控级联的综合方法，并鉴定了一种与疾病进展相关的蛋白质。使用染色质免疫沉淀和基因组平铺阵列，将转录因子结合位点的全基因组图谱与基因表达谱相结合，以鉴定参与雌激素增殖反应 (E2) 的基因。使用 RNA 干扰，选定的 ERα 和 c-MYC 基因靶标被敲低，以确定 E2 刺激细胞增殖的介质。组织微阵列筛查显示，表观遗传因子（E2 诱导组蛋白变体 H2A.Z）的高表达与淋巴结转移和乳腺癌生存率降低显着相关。 H2A.Z 水平的检测独立地提高了目前临床使用的生物标志物的预后能力。这种综合方法加速了与乳腺癌进展相关的分子的识别，对诊断和治疗干预具有影响，并且可应用于多种癌症。
We demonstrate an integrated approach to the study of a transcriptional regulatory cascade involved in the progression of breast cancer and we identify a protein associated with disease progression. Using chromatin immunoprecipitation and genome tiling arrays, whole genome mapping of transcription factor-binding sites was combined with gene expression profiling to identify genes involved in the proliferative response to estrogen (E2). Using RNA interference, selected ERα and c-MYC gene targets were knocked down to identify mediators of E2-stimulated cell proliferation. Tissue microarray screening revealed that high expression of an epigenetic factor, the E2-inducible histone variant H2A.Z, is significantly associated with lymph node metastasis and decreased breast cancer survival. Detection of H2A.Z levels independently increased the prognostic power of biomarkers currently in clinical use. This integrated approach has accelerated the identification of a molecule linked to breast cancer progression, has implications for diagnostic and therapeutic interventions, and can be applied to a wide range of cancers.
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