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Heat-shock factor 1 associated with increased metastasis, mortality
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Increased expression of genes activated by a transcription factor called heat-shock factor 1 was strongly linked with metastasis and mortality in patients with breast, colon and lung cancers, according to study results.
The finding could help researchers identify a gene profile predictive of patient outcomes and response to treatment. It also could guide the development of therapeutics to target multiple cancer types, the researchers wrote.
In normal cells, an assortment of stressors — such as heat or hypoxia — activate heat-shock factor 1 (HSF1), which leads to increased expression of ‘heat-shock’ or chaperone proteins that maintain protein homeostasis in stressed cells. However, prior studies have indicated that in cancer cells, HSF1 initiates a different transcriptional program that enables particularly aggressive cancer types.
“This cancer program is commonly activated in a wide variety of human malignancies,” the researchers wrote. “It is strongly associated with metastasis and death in at least the three cancers responsible for [approximately] 30% of all cancer-related deaths worldwide: those of the breast, colon and lung. The very broad range of tumors in which we see immunohistochemical evidence of HSF1 activation suggests it will play a pervasive role throughout tumor biology.”
To investigate the HSF1-regulated transcriptional program in cancer and how it relates to the classical heat-shock response, the researchers identified changes in the HSF1 transcriptional program that occurred during transformation and triggered the varying malignant potentials of cancer cells.
The researchers subjected human breast cancer cell samples to chromatin immunoprecipitation coupled with massively parallel DNA sequencing, which exposed a diverse transcriptional network coordinated by HSF1 in the highly malignant cells. Researchers expanded analysis of this HSF1 cancer program to multiple independent gene expression data sets that included outcomes data for patients with breast, colon and lung cancer.
According to study results, cancer-specific genes in the HSF1 transcriptional program support oncogenic processes, including cell-cycle regulation, signaling, metabolism, adhesion and translation. The HSF1 cancer program was observed to be active in breast, colon and lung tumors isolated directly from human patients, and it was strongly associated with metastasis and death.
“By enabling oncogenesis, the activation of this ancient prosurvival mechanism thereby actually impairs survival of the host,” the researchers wrote. “HSF1 activation in a particular tumor may reflect the degree to which accumulated oncogenic mutations have disrupted normal physiology even before overt invasion or metastasis occurs. This interpretation would explain the impressively broad prognostic value of our HSF1-cancer signature across disparate cancers and even at early stages of disease.”
Disclosure: The researchers report no relevant financial disclosures.
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