Abstract
Heat shock transcription factor 1 (HSF1), a key regulator of the heat-shock response, is deregulated in many cancers. HSF1 can mediate cancer cell survival and metastasis. High levels of HSF1 have been associated with poor prognosis in breast cancer. The nature of HSF1 upregulation needs to be validated in different cohorts to further validate its prognostic utility in breast cancer.We first evaluated its expression in a cohort of breast cancer tissue microarrays with Oncotype DX recurrence scores available using immunohistochemistry. To further confirm the clinical relevance and prognostic impact, mutational and methylation status of the gene were also assessed in The Cancer Genome Atlas and publically available microarray datasets.Immunohistochemical analysis showed that HSF1 expression is independent of Oncotype DX high recurrence score in ER-positive node-negative patients. Analysis of The Cancer Genome Atlas data revealed upregulation of HSF1 is not due to methylation or mutation. HSF1 copy number variations and amplifications (15%) were not associated with survival. In publicly available microarray datasets, a prognostic impact was observed in ER-positive tumors, but not in ER-negative tumors. Patients with ER-positive tumors with high HSF1 levels were associated with shorter overall survival (P = 0.00045) and relapse-free survival (P = 0.0057). In multivariable analysis, HSF1 remained a significant prognostic parameter.The mRNA expression levels of HSF1 in ER-positive breast cancer are associated with both shorter relapse-free and overall survival. This prognostic impact is specific to mRNA expression, but stayed insignificant by protein expression or by analyzing amplification events.
Highlights
Cells and organisms respond to stress by inducing heat shock proteins which act as molecular chaperones to restore protein homeostasis [1,2,3,4]
Upregulation Heat shock transcription factor 1 (HSF1) protein levels is independent of Oncotype DX high recurrence scores
To validate the prognostic relevance of HSF1 observed by Santagata et al, we assessed the expression levels of HSF1 in a tissue microarray (TMA) cohort of patients with Oncotype DX scores using a commercially available antibody [16]
Summary
Cells and organisms respond to stress by inducing heat shock proteins which act as molecular chaperones to restore protein homeostasis [1,2,3,4]. This adaptive mechanism is controlled by heat shock transcription factor (HSF1). When this transcription factor is activated, it gets phosphorylated, trimerized, and translocates to the nucleus. In the nucleus, it binds to specific DNA sequence motifs (known as heat shock elements) leading to the synthesis of heat shock proteins. Mitotic cells are unable to induce expression of heat shock genes and are susceptible to protein damaging stress
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