Heat shock factor 1 induces cancer stem cell phenotype in breast cancer cell lines

Bin Wang, Chung-Wei Lee, Abigail Witt, Ankita Thakkar, Tan A. Ince

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.