Panaccione Alex, Guo Yan, Yarbrough Wendell G, Ivanov Sergey V
Department of Surgery, Section of Otolaryngology, Yale School of Medicine, New Haven, CT.
Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN.
Clin Breast Cancer. 2017 Jul;17(4):298-306.e7. doi: 10.1016/j.clbc.2017.01.007. Epub 2017 Jan 27.
We previously characterized in salivary adenoid cystic carcinoma (ACC) a novel population of cancer stem cells (CSCs) marked by coexpression of 2 stemness genes, sex-determining region Y (SRY)-related HMG box-containing factor 10 (SOX10) and CD133. We also reported that in ACC and basal-like breast carcinoma (BBC), a triple-negative breast cancer subtype, expression of SOX10 similarly demarcates a highly conserved gene signature enriched with neural stem cell genes. On the basis of these findings, we hypothesized that BBC might be likewise driven by SOX10-positive (SOX10)/CD133 cells with neural stem cell properties.
To validate our hypothesis on clinical data, we used a novel approach to meta-analysis that merges gene expression data from independent breast cancer studies and ranks genes according to statistical significance of their coexpression with the gene of interest. Genes that showed strong association with CD133/PROM1 as well as SOX10 were validated across different platforms and data sets and analyzed for enrichment with genes involved in neurogenesis.
We identified in clinical breast cancer data sets a highly conserved SOX10/PROM1 gene signature that contains neural stem cell markers common for Schwann cells, ACC, BBC, and melanoma. Identification of tripartite motif-containing 2 (TRIM2), TRIM29, MPZL2, potassium calcium-activated channel subfamily N member 4 (KCNN4), and V-set domain containing T cell activation inhibitor 1 (VTCN1)/B7 homolog 4 (B7H4) within this signature provides insight into molecular mechanisms of CSC maintenance.
Our results suggest that BBC is driven by SOX10/CD133 cells that express neural stem cell-specific markers and share molecular similarities with CSCs of neural crest origin. Our study provides clinically relevant information on possible drivers of these cells that might facilitate development of CSC-targeting therapies against this cancer distinguished with poor prognosis and resistance to conventional therapies.
我们之前在涎腺腺样囊性癌（ACC）中鉴定出了一群新的癌症干细胞（CSC），其特征是共同表达两个干性基因，即性别决定区Y（SRY）相关的含高迁移率族盒因子10（SOX10）和CD133。我们还报道，在ACC和三阴性乳腺癌的一种亚型基底样乳腺癌（BBC）中，SOX10的表达同样界定了一个高度保守的基因特征，该特征富含神经干细胞基因。基于这些发现，我们推测BBC可能同样由具有神经干细胞特性的SOX10阳性（SOX10+）/CD133细胞驱动。
为了在临床数据上验证我们的假设，我们采用了一种新的荟萃分析方法，该方法合并了来自独立乳腺癌研究的基因表达数据，并根据基因与感兴趣基因共表达的统计显著性对基因进行排名。与CD133/PROM1以及SOX10显示出强关联的基因在不同平台和数据集中得到验证，并分析其与神经发生相关基因的富集情况。
我们在临床乳腺癌数据集中鉴定出一个高度保守的SOX10/PROM1基因特征，其中包含施万细胞、ACC、BBC和黑色素瘤共有的神经干细胞标志物。在这个特征中鉴定出含三联基序蛋白2（TRIM2）、TRIM29、MPZL2、钾钙激活通道亚家族N成员4（KCNN4）以及含V结构域的T细胞激活抑制因子1（VTCN1）/B7同源物4（B7H4），这为深入了解CSC维持的分子机制提供了线索。
我们的结果表明，BBC由表达神经干细胞特异性标志物且与神经嵴来源的CSC具有分子相似性的SOX10/CD133细胞驱动。我们的研究提供了关于这些细胞可能的驱动因素的临床相关信息，这可能有助于开发针对这种预后不良且对传统疗法耐药的癌症的CSC靶向治疗方法。
