Cell-type specific responses to chemotherapeutics in breast cancer. Homo sapiens

Recent studies have identified clinical subtypes of breast tumors that arise from different cell types and have different outcomes in response to chemotherapy. Tumors derived from basal epithelium have a poorer prognosis than tumors derived from luminal epithelium. To gain insight into differences underlying this disparity, we treated cell lines derived from basal epithelium (immortalized human mammary epithelial cells) and those derived from luminal epithelium (MCF-7 and ZR-75-1) with two chemotherapeutics commonly used in the treatment of breast cancer. Treatment doses for doxorubicin (DOX) and 5-fluorouracil (5FU) were selected to cause comparable cytotoxicity across all four cell lines. The predominant gene expression in each of the four cell lines was a general stress response, but distinct gene expression patterns were observed depending upon cell type. Both cell types up-regulated DNA damage response genes such as p21waf1, but the response in the luminal cells was much more dramatic and included many p53-regulated genes. Luminal cell lines down-regulated a large number of cell cycle regulators and other genes involved in cellular proliferation, while basal cell lines down-regulated a smaller set of genes, many of which are involved in cellular differentiation. These results were compared to gene expression data from tumor samples collected before and after treatment with DOX or 5FU/mitomycin C. Similarities between the in vitro and in vivo responses validate this model for studying gene expression responses to chemotherapy in these cell types. Understanding cell-type specific responses to chemotherapeutics will help in tailoring treatment to patients based upon tumor characteristics. Keywords = breast cancer Keywords = chemotherapy Keywords = gene expression Keywords = microarray Keywords = stress response Keywords: time-course

已有研究表明，乳腺癌存在源自不同细胞类型、化疗应答与预后均存在差异的临床亚型。其中，源自基底上皮（basal epithelium）的肿瘤，其预后较管腔上皮（luminal epithelium）来源的肿瘤更差。为探究该预后差异背后的分子机制，本研究采用两种临床常用乳腺癌化疗药物，分别处理基底上皮来源细胞系（永生化人乳腺上皮细胞，immortalized human mammary epithelial cells）与管腔上皮来源细胞系（MCF-7、ZR-75-1）。本研究选定的多柔比星（doxorubicin，DOX）与5-氟尿嘧啶（5-fluorouracil，5FU）给药剂量，可在四种细胞系中诱导相当水平的细胞毒性。四种细胞系的核心基因表达特征均为普遍应激反应，但不同细胞类型呈现出截然不同的基因表达模式。两种细胞类型均会上调DNA损伤应答基因（如p21waf1），但管腔细胞的应答更为显著，且涵盖众多p53调控基因。管腔细胞系会下调大量细胞周期调控因子及其他参与细胞增殖的基因，而基底细胞系仅下调少量基因，其中多数与细胞分化相关。本研究将上述实验结果与DOX或5FU/丝裂霉素C（mitomycin C）治疗前后采集的肿瘤样本基因表达数据进行了对比。体外（in vitro）与体内（in vivo）应答的一致性，验证了该细胞模型可用于研究此类细胞对化疗的基因表达应答。解析细胞类型特异性的化疗应答机制，将有助于根据肿瘤特征为患者制定个体化治疗方案。关键词：乳腺癌、化疗、基因表达、基因芯片（microarray）、应激反应（stress response）、时间进程（time-course）