Heat shock factor 1 induces cancer stem cell phenotype in breast cancer cell lines.
Heat shock factor 1 induces cancer stem cell phenotype in breast cancer cell lines.
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DOI：
10.1007/s10549-015-3521-1
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发表时间：
2015-08
影响因子：
3.8
通讯作者：
Ince TA
中科院分区：
文献类型：
--
作者：
Wang B;Lee CW;Witt A;Thakkar A;Ince TA
热休克因子1（Heat shock factor 1，HSF 1）是调节热休克蛋白（Heat shock proteins，HSPs）的主要转录因子，近年来发现HSF 1在调节细胞对热休克以外的多种应激反应中发挥更广泛的作用，我们以前发现HSF 1高表达与肺癌、乳腺癌和结肠癌的预后不良有关。然而，重要的是，在这些研究中与不良结果相关的HSF 1特征与热休克反应无关，这表明与高HSF表达相关的肿瘤结果可能是由于应激反应以外的过程。因此，我们探讨了HSF 1高表达是否与癌症干细胞（CSC）表型相关的问题。为此，我们通过流式细胞术和免疫荧光检测了HSF 1与CSC表型的相关性。此外，我们评估了乳腺癌细胞系中HSF 1过表达和敲低对球体形成和CSC标志物表达的影响。在这里，我们报告的结果表明，高HSF 1不仅与CSC标志物的表达，但诱导型HSF 1过表达增强和HSF 1敲低抑制CSC表型。此外，HSF 1表达赋予对化疗药物的抗性并增加CSC频率。总之，我们的研究表明，可能导致人类肿瘤不良结局的潜在HSP非依赖性HSF 1驱动机制之一涉及CSC表型的调节。因此，HSF 1的治疗性抑制可能是靶向人类肿瘤中CSC的一种途径。本文的在线版本（doi：10.1007/s10549-015-3521-1）包含补充材料，可供授权用户使用。
Heat shock factor 1 (HSF1) has long been recognized as the master transcription factor that regulates heat shock proteins (HSPs). More recently HSF1 has been associated with a broader role in regulating response to a variety of cellular stresses beyond heat-shock. We previously found that high HSF1 expression is associated with poor outcome in lung, breast and colon cancers. Importantly, however, the HSF1 signature correlated with poor outcome in these studies was not related to the heat shock response, which suggested that tumor outcome associated with high HSF expression may be due to processes other than stress response. Hence, we explored the question whether high HSF1 expression might be associated with the cancer stem cell (CSC) phenotype. To do so, we examined the association of HSF1 with CSC phenotype by FACS and immunofluorescence. In addition, we evaluated the effects of HSF1 over-expression and knock-down on sphere formation and CSC marker expression in breast cancer cell lines. Here, we report results demonstrating that high HSF1 not only correlates with CSC marker expression, but inducible HSF1 over-expression augments and HSF1 knock-down inhibits CSC phenotype. Furthermore, HSF1 expression confers resistance to chemotherapeutic drugs and increases CSC frequency. In conclusion, our study indicates that one of the potential HSP-independent HSF1 driven mechanisms that may contribute to poor outcome in human tumors involves regulation of the CSC phenotype. Hence, therapeutic inhibition of HSF1 may be one route to target CSCs in human tumors. The online version of this article (doi:10.1007/s10549-015-3521-1) contains supplementary material, which is available to authorized users.