Abstract A23: Cell autonomous and nonautonomous activities of heat shock factor 1 support tumor initiation, progression, and metastasis

The heat-shock response is a powerful transcriptional program which acts genome-wide, not only to restore the normal protein folding through the induction of heat shock proteins (HSP), but to re-shape global cellular pathways controlling survival, growth and metabolism. In mammals, this response is regulated primarily by the Heat Shock Factor 1 (HSF1) transcription factor. We have previously shown that HSF1 plays a fundamental role in tumorigenesis, by promoting the survival and malignance of tumor cells, both in tissue culture and in mouse models of cancer [1]. Recently we demonstrated that HSF1 exerts its role by activating a unique transcriptional program in the cancer cells, that is distinct from the one activated during heat shock [2]. In breast cancer and several other types of carcinoma, we found that high HSF1 protein levels and activation of the HSF1-dependent transcriptional program are associated with poor clinical outcome [3]. Here we show that HSF1 is activated not only in the tumor cells, but also in the stromal cells infiltrating the tumor. Examining human patient samples, we find immunohistochemical evidence for activation of HSF1 in the stroma. Using mouse xenograft models and in vitro co-culture we show that HSF1 in the stroma supports tumor cell growth. Finally, expression profiling and analysis of the DNA binding pattern of HSF1 in tumors and in cell culture indicates that stromal HSF1 supports tumorigenesis by activating a unique, stroma-specific transcriptional program. Taken together, our data suggests that HSF1 acts in the cancer cells and in the stroma to activate distinct, yet complimentary transcriptional programs that will facilitate tumor initiation, progression and metastasis. References 1. Dai, C., et al., Heat shock factor 1 is a powerful multifaceted modifier of carcinogenesis. Cell, 2007. 130(6): p. 1005-18. 2. Mendillo, M.L., et al., HSF1 drives a transcriptional program distinct from heat shock to support highly malignant human cancers. Cell, 2012. 150(3): p. 549-62. 3. 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. Citation Format: Ruth Scherz-Shouval, Sandro Santagata, Martina Koeva, Luke Whitesell, Susan Lindquist. Cell autonomous and nonautonomous activities of heat shock factor 1 support tumor initiation, progression, and metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A23.