Characterization of Cell Lines Derived from Breast Cancers and Normal Mammary Tissues for the Study of the Intrinsic Molecular Subtypes

Five molecular subtypes (Luminal A/B, HER2-enriched, Basal-like, and Claudin-low) with clinical implications have been identified. In this report, we evaluated molecular and phenotypic relationships of a large in vitro panel of human breast cancer cell lines (BCCLs), human mammary fibroblasts (HMFs) and human mammary epithelial cells (HMECs) with (1) breast tumors, (2) normal breast cell-enriched subpopulations and (3) human embryonic stem cells (hESCs) and bone marrow-derived mesenchymal stem cells (hMSC). First, by integrating genomic data of 337 breast samples with 93 cell lines we were able to identify all the intrinsic tumor subtypes in vitro, except for the Luminal A. Secondly, we observed that cell lines recapitulate the differentiation hierarchy observed in the mammary gland, with Claudin-low BCCLs and HMFs cells showing a stromal phenotype, HMECs showing a mammary stem cell/bipotent progenitor phenotype, Basal-like cells showing a luminal progenitor phenotype, and Luminal B cells showing a luminal phenotype. Thirdly, we identified Basal-like and highly migratory Claudin-low subpopulations of cells within a subset of triple-negative BCCLs (SUM149PT, HCC1143 and HCC38). Interestingly, both subpopulations within SUM149PT where found to have Tumor Initiating Cell (TIC) features, but the Basal-like subpopulation grew faster than the Claudin-low subpopulation. Finally, Claudin-low BCCLs were found to resemble the phenotype of hMSCs, whereas hESCs cells were found to have an epithelial phenotype without basal and luminal differentiation. The results presented here should help improve our understanding of the cell line model system through the appropriate pairing of cell lines with relevant in vivo tumor and normal cell counterparts. reference x sample

现已鉴定出五种具备临床意义的分子亚型：腔面A/B型（Luminal A/B）、HER2富集型（HER2-enriched）、基底样型（Basal-like）以及紧密连接蛋白低表达型（Claudin-low）。本研究评估了大型体外细胞库中人乳腺癌细胞系（human breast cancer cell lines, BCCLs）、人乳腺成纤维细胞（human mammary fibroblasts, HMFs）及人乳腺上皮细胞（human mammary epithelial cells, HMECs）与以下三类样本的分子及表型关联：(1) 乳腺肿瘤组织；(2) 富集正常乳腺细胞的亚群；(3) 人胚胎干细胞（human embryonic stem cells, hESCs）及骨髓间充质干细胞（bone marrow-derived mesenchymal stem cells, hMSC）。首先，通过整合337份乳腺样本与93株细胞系的基因组数据，本研究成功在体外体系中鉴定出除腔面A型以外的所有固有肿瘤分子亚型。其次，本研究发现细胞系能够复刻乳腺组织中的分化层级：紧密连接蛋白低表达型乳腺癌细胞系（Claudin-low BCCLs）与人乳腺成纤维细胞（HMFs）呈现间质表型，人乳腺上皮细胞（HMECs）呈现乳腺干细胞/双能祖细胞表型，基底样型细胞（Basal-like）呈现腔面祖细胞表型，而腔面B型细胞则呈现腔面表型。第三，本研究在部分三阴性乳腺癌细胞系（SUM149PT、HCC1143及HCC38）中鉴定出两类细胞亚群：基底样型亚群与高迁移性紧密连接蛋白低表达型亚群。值得注意的是，SUM149PT细胞系内的两类亚群均具备肿瘤起始细胞（Tumor Initiating Cell, TIC）特征，但基底样型亚群的增殖速度快于紧密连接蛋白低表达型亚群。最后，本研究发现紧密连接蛋白低表达型乳腺癌细胞系（Claudin-low BCCLs）的表型与骨髓间充质干细胞（hMSC）相似，而人胚胎干细胞（hESCs）则呈现上皮表型，不具备基底及腔面分化特性。本研究结果将通过将细胞系与对应的体内肿瘤及正常细胞样本进行合理匹配，助力学界加深对细胞系模型体系的认知。参考样本x