Abstract 4731: High level of nuclear heat-shock factor 1 is associated with aggressive disease and suggests targets for therapy in endometrial carcinoma

Abstract

Abstract Background: The transcriptional regulator heat-shock transcription factor 1 (HSF1) has recently been linked to progression of breast cancer (Santagata, PNAS 2011). HSF1 is a regulator of cellular response to stress and drives the production of heat shock proteins (HSPs). The role of HSF1 to promote tumor cell survival has been demonstrated in hsf1 knockout mice (Dai, Cell 2007). Furthermore, recent identification of a specific role of HSF1 in cancer progression has led to new relevance of HSF1 as a marker both for prognosis and as a predictive marker. The role of HSF1 in endometrial cancer has so far been unexplored. Methods: A total of 823 lesions from endometrial carcinoma precursors, primary tumors and metastases were prospectively collected and explored for HSF1 protein expression in relation to established markers for aggressive disease and survival. Transcriptional alterations related to HSF1 protein level were investigated by microarray analysis for 224 freshly frozen samples in parallel. Results: High expression of HSF1 protein in endometrial carcinoma is significantly associated with non-endometrioid histology, high grade, ERα loss and poor survival (all p-values ≤0.02). Also among ERα-positive patients presumed to have good prognosis, high expression of HSF1 is correlated with poor survival (p=0.02). HSF1 mRNA and protein levels increase significantly from primary tumors to metastases (p<0.03). HSF1-related gene signatures were explored. Such signatures increase from complex atypical hyperplasias through primary tumors to metastatic lesion and were also found to have prognostic value. HSF1 immunohistochemistry suggests the use of HSP90 inhibitiors as potential novel therapeutic approach in cases with high protein expression of HSF1. Conclusion: We demonstrate for the first time in endometrial cancer that high expression of HSF1 and measures for transcriptional activation of HSF1 associates with poor outcome, progression from precursor lesions through primary tumors to metastatic lesions. Also, HSP90 inhibitors are suggested as potential new targeted therapeutics for cases with high HSF1 levels in particular. 1. Santagata,S., et al., High levels of nuclear heat-shock factor 1 (HSF1) are associated with poor prognosis in breast cancer. Proc Natl Acad Sci U S A, 2011. 108(45):p. 18378-83. 2. Dai,C., et al., Heat shock factor 1 is a powerful multifaceted modifier of carcinogenesis. Cell, 2007. 130(6): p. 1005-18. Citation Format: Hilde Engerud, Ingvild Løberg Tangen, Anna Berg, Kanthida Kusonmano, Ingunn Stefansson, Helga B. Salvesen, Camilla Krakstad. High level of nuclear heat-shock factor 1 is associated with aggressive disease and suggests targets for therapy in endometrial carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4731. doi:10.1158/1538-7445.AM2014-4731