Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, USA.
BMC Med. 2009 Dec 14;7:77. doi: 10.1186/1741-7015-7-77.
Polyamines regulate important cellular functions and polyamine dysregulation frequently occurs in cancer. The objective of this study was to use a systems approach to study the relative effects of PG-11047, a polyamine analogue, across breast cancer cells derived from different patients and to identify genetic markers associated with differential cytotoxicity.
A panel of 48 breast cell lines that mirror many transcriptional and genomic features present in primary human breast tumours were used to study the antiproliferative activity of PG-11047. Sensitive cell lines were further examined for cell cycle distribution and apoptotic response. Cell line responses, quantified by the GI50 (dose required for 50% relative growth inhibition) were correlated with the omic profiles of the cell lines to identify markers that predict response and cellular functions associated with drug sensitivity.
The concentrations of PG-11047 needed to inhibit growth of members of the panel of breast cell lines varied over a wide range, with basal-like cell lines being inhibited at lower concentrations than the luminal cell lines. Sensitive cell lines showed a significant decrease in S phase fraction at doses that produced little apoptosis. Correlation of the GI50 values with the omic profiles of the cell lines identified genomic, transcriptional and proteomic variables associated with response.
A 13-gene transcriptional marker set was developed as a predictor of response to PG-11047 that warrants clinical evaluation. Analyses of the pathways, networks and genes associated with response to PG-11047 suggest that response may be influenced by interferon signalling and differential inhibition of aspects of motility and epithelial to mesenchymal transition.
多胺调节重要的细胞功能，多胺失调经常发生在癌症中。本研究的目的是使用系统方法研究多胺类似物 PG-11047 在源自不同患者的乳腺癌细胞中的相对作用，并鉴定与细胞毒性差异相关的遗传标记。
使用一组 48 个乳腺癌细胞系，这些细胞系反映了原发性人乳腺癌中存在的许多转录和基因组特征，来研究 PG-11047 的抗增殖活性。对敏感细胞系进行细胞周期分布和凋亡反应的进一步检查。通过 GI50（抑制相对生长 50%所需的剂量）量化细胞系的反应，将其与细胞系的组学图谱相关联，以鉴定预测反应的标记物和与药物敏感性相关的细胞功能。
抑制面板中乳腺癌细胞系成员生长所需的 PG-11047 浓度范围很广，基底样细胞系的抑制浓度低于腔细胞系。敏感细胞系在产生很少凋亡的剂量下，S 期分数明显下降。将 GI50 值与细胞系的组学图谱相关联，确定了与反应相关的基因组、转录组和蛋白质组变量。
开发了一个 13 个基因转录标记集作为对 PG-11047 反应的预测因子，值得临床评估。对与 PG-11047 反应相关的途径、网络和基因的分析表明，反应可能受到干扰素信号和运动和上皮间质转化方面的差异抑制的影响。
