目的:CD133,一种肿瘤干细胞(CSC)标记,据报道,在三阴性乳腺癌(BC)中,与治疗耐药性和较差的生存率有关。然而,ER阳性/HER2阴性(ER+/HER2-)BC中CD133表达的临床意义,最丰富的亚型,仍然未知。
方法:来自乳腺癌国际组织分子分类学(METABRIC,n=1904)和癌症基因组图谱(TCGA,n=1065)用于获得生物学变量和基因表达数据。
结果:上皮细胞是大量BC中CD133基因表达的唯一来源。CD133高ER+/HER2-BC与CD24、NOTCH1、DLL1和ALDH1A1基因表达相关,以及WNT/β-Catenin,刺猬,和Notch信号通路,CSC的所有特征。与CSC表型一致,CD133-lowBC富含与细胞增殖相关的基因集,例如G2M检查点,MYC目标V1、E2F目标,和Ki67基因表达。CD133低BC也与DNA修复相关基因的富集有关,如BRCA1、E2F1、E2F4、CDK1/2。另一方面,CD133-high肿瘤有促炎微环境,免疫细胞的活性更高,与炎症和免疫反应相关的基因表达较高。最后,在GSE25066队列中,CD133-high肿瘤在新辅助化疗后具有更好的病理完全缓解,在TCGA和METABRIC队列中均具有更好的无病生存期和总生存期。
结论:CD133高ER+/HER2-BC与CSC表型相关,如细胞增殖和DNA修复减少,而且炎症也增强了,对新辅助化疗反应较好,预后较好。
OBJECTIVE: CD133, a cancer stem cells (CSC) marker, has been reported to be associated with treatment resistance and worse survival in triple-negative breast cancer (BC). However, the clinical relevance of
CD133 expression in ER-positive/HER2-negative (ER + /HER2-) BC, the most abundant subtype, remains unknown.
METHODS: The BC cohorts from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC, n = 1904) and The Cancer Genome Atlas (TCGA, n = 1065) were used to obtain biological variables and gene expression data.
RESULTS: Epithelial cells were the exclusive source of
CD133 gene expression in a bulk BC.
CD133-high ER + /HER2- BC was associated with CD24, NOTCH1, DLL1, and ALDH1A1 gene expressions, as well as with WNT/β-Catenin, Hedgehog, and Notch signaling pathways, all characteristic for CSC. Consistent with a CSC phenotype, CD133-low BC was enriched with gene sets related to cell proliferation, such as G2M Checkpoint, MYC Targets V1, E2F Targets, and Ki67 gene expression. CD133-low BC was also linked with enrichment of genes related to DNA repair, such as BRCA1, E2F1, E2F4, CDK1/2. On the other hand,
CD133-high tumors had proinflammatory microenvironment, higher activity of immune cells, and higher expression of genes related to inflammation and immune response. Finally, CD133-high tumors had better pathological complete response after neoadjuvant chemotherapy in GSE25066 cohort and better disease-free survival and overall survival in both TCGA and METABRIC cohorts.
CONCLUSIONS: CD133-high ER + /HER2- BC was associated with CSC phenotype such as less cell proliferation and DNA repair, but also with enhanced inflammation, better response to neoadjuvant chemotherapy and better prognosis.