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

Abstract

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.Electronic supplementary materialThe online version of this article (doi:10.1007/s10549-015-3521-1) contains supplementary material, which is available to authorized users.

Loss of AMPK activation promotes the invasion and metastasis of pancreatic cancer through an HSF1‐dependent pathway

“…In breast cancer, nearly 80% of in situ and invasive breast carcinomas expressed high levels of HSF1, which was associated with a high histological grade, a larger tumor size, and nodal involvement; those with HSF1‐positive tumors had significantly reduced survival rates compared with women with HSF1‐negative tumors (Santagata et al ., ). A subsequent study revealed that in breast cancer cell lines, the overexpression of HSF1 induced an augmentation of the cancer stem cell markers and conferred resistance to chemotherapeutic drugs (Wang et al ., ). Here, we showed that pancreatic cancer expressed a high level of HSF1, which is similar to other cancers.…”

Heat Shock Factor 1 Depletion Sensitizes A172 Glioblastoma Cells to Temozolomide via Suppression of Cancer Stem Cell-Like Properties

“…HSF1 has also been shown to be involved in hepatocellular carcinoma development [3], as well as induction of a CSC-like phenotype in breast cancer cells [5]. A greater understanding of CSCs will be important for the diagnosis and treatment of cancer as well as for future drug development [21,22].…”

What does not kill a tumour may make it stronger:in silicoInsights into Chemotherapeutic Drug Resistance

“…Consequently, if there exists a subpopulation of slow-cycling cells in a tumour, this subpopulation is more likely to survive chemotherapy and proliferate post treatment, despite having a slower production rate. Such a slow-cycling subpopulation may comprise CSC-like cells, as slow-cycling cells have been linked to cancer stem cells [40],which in turn have been conferred with reduced sensitivity to chemotherapeutic drugs [78]. Previous research indicates that cancer cells may obtain stem-cell like traits [16], in fact non-stem cancer cells may convert into CSC-like cells seemingly spontaneously, as demonstrated in vivo by Chaffer et al [12].…”

“…Inhibiting Hsp27, Hsp70, Hsp90 has been hypothesised as part of future treatment plans [29,65] and moreover Hsp70 has been suggested as a factor to prognostically evaluate the risk of disease recurrence [45]. The heat shock factor 1 protein (HSF1) regulates Hsps [65,78], and HSF1 overexpression is linked to poor prognosis in breast, lung and colon cancers, an increase in intratumoural cancer stem cells proportions and chemotherapeutic drug resistance [78]. Specifically, cells with high HSF1 levels have displayed increased paclitaxel resistance [78].…”

“…The heat shock factor 1 protein (HSF1) regulates Hsps [65,78], and HSF1 overexpression is linked to poor prognosis in breast, lung and colon cancers, an increase in intratumoural cancer stem cells proportions and chemotherapeutic drug resistance [78]. Specifically, cells with high HSF1 levels have displayed increased paclitaxel resistance [78]. Although cellular Hsp expression and activity have been linked to anti-cancer drug resistance, the details of these mechanisms are yet to be elucidated [76].…”