Differentially expressed genes regulating the progression of ductal carcinoma in situ to invasive breast cancer.
Differentially expressed genes regulating the progression of ductal carcinoma in situ to invasive breast cancer.
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DOI：
10.1158/0008-5472.can-12-0636
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发表时间：
2012-09-01
期刊：
影响因子：
11.2
通讯作者：
Allred DC
中科院分区：
文献类型：
--
作者：
Lee S;Stewart S;Nagtegaal I;Luo J;Wu Y;Colditz G;Medina D;Allred DC
导管原位癌(DCIS)向浸润性乳腺癌(IBC)发展的分子机制目前仍不清楚。我们使用人类DCIS(n=53)和IBC(n=51)的基因表达谱来发现也可能调节进展的独特表达的基因。共有470个差异表达基因(≥2倍；p<；0.05)。参与细胞外基质合成和组织的基因在IBC上皮细胞中的表达升高尤为显著。确定了这些基因与文献中9项类似研究的重叠程度，以帮助确定它们的潜在重要性，导致74项在≥2研究中显示重叠(平均3.6项研究/基因；范围2-8项研究)。在本研究和两个类似的独立研究中，使用等级聚类，74基因图谱分别能够正确地对96%、93%和85%的样本进行分类。为了在体内研究DCIS向IBC转化的过程，我们将表达特定基因的人DCIS细胞系引入“乳腺导管内DCIS”(Mind)异种移植模型。通过抑制四个通常在DCIS临床样本中升高的基因，包括蛋白酶抑制剂(Csta)和参与细胞黏附和信号转导的基因(FAT1、DST和TMEM45A)，异种移植向IBC的进展显著增加，强烈表明它们通常具有抑制进展的功能。综上所述，我们已经确定了人类DCIS和IBC独特的基因表达谱，其中包括调控肿瘤进展的新基因。靶向这些基因中的一部分可能会改善DCIS的检测、诊断和治疗。
Molecular mechanisms mediating the progression of ductal carcinoma in situ (DCIS) to invasive breast cancer (IBC) remain largely unknown. We used gene expression profiling of human DCIS (n=53) and IBC (n=51) to discover uniquely expressed genes that may also regulate progression. There were 470 total differentially expressed genes (≥ 2 fold; p<0.05). Elevated expression of genes involved in synthesis and organization of extracellular matrix was particularly prominent in the epithelium of IBC. The degree of overlap of the genes with nine similar studies in the literature was determined to help prioritize their potential importance, resulting in 74 showing overlap in ≥ 2 studies (average 3.6 studies/gene; range 2-8 studies). Using hierarchical clustering, the 74-gene profile was able to correctly categorize 96%, 93%, and 85% of samples in this study and two similar independent studies, respectively. To study the progression of DCIS to IBC in vivo, we introduced human DCIS cell lines engineered to express specific genes into a “mammary intraductal DCIS” (MIND) xenograft model. Progression of xenografts to IBC was dramatically increased by suppressing four genes that were usually elevated in clinical samples of DCIS, including a protease inhibitor (CSTA) and genes involved in cell adhesion and signaling (FAT1, DST, and TMEM45A), strongly suggesting that they normally function to suppress progression. In summary, we have identified unique gene expression profiles of human DCIS and IBC, which include novel genes regulating tumor progression. Targeting some of these genes may improve the detection, diagnosis, and therapy of DCIS.