Opposing Effects Of Heat Shock Factors 1 And 2 On Prostate Cancer Invasion

Prostate cancer (PrCa) is the most common malignancy in Western countries and account for the second highest mortality rate of all cancer forms in males. Specifically in late stage castration-resistant PrCa (CRPC), the signaling pathways that contribute to invasion and metastasis are poorly understood. The heat shock factors (HSFs) are a family of multifaceted transcriptional regulators that govern survival upon proteotoxic stress. This is achieved, mainly via HSF1, through up-regulation of genes critical for endurance under stressful conditions. Interestingly, the capacity to withstand stress is also readily utilized by cancer cells, which face a variety of stressful conditions. It thus seems that HSF1 allows cancer cells to rapidly modify their physiology, metabolism and protein homeostasis, thereby facilitating oncogenesis. Moreover, lack of HSF1 reduces the susceptibility of mice to mutation- or carcinogen-driven tumors and reduces the growth of human cancer cell lines. Recently, examination of a cohort of breast cancer patients showed that high expression of HSF1 correlated with decreased survival rate, highlighting the clinical significance of HSF1. The aim of this study was to elucidate novel molecular pathways that contribute to the detrimental development of CRPC. Our initial in silico analyses showed that in PrCa, HSF1 expression levels correlate with poor survival and high Gleason grades. Most intriguingly, HSF2, thus far unassociated with cancer, showed decreased expression in the same set of tumors. We used real time live cell imaging in combination with endpoint immunofluorescent stainings of 3-dimensional (3D) organotypic cultures of PC-3 cells that spontaneously undergo an invasive switch, leading to the disintegration of epithelial structures and the basal lamina, and formation of invadopodia and invasive structures. This model demonstrates the highly dynamic nature of epithelial plasticity, and the functional studies of 3D cultures implied roles for both of these factors in the invasive behavior of tumors. In fact, we found that HSF1 and HSF2 show opposing effect on tumor cell invasion. Tumor spheroids lacking HSF1 grew more slowly, were more differentiated and polarized, and were devoid of any invasive behavior. In contrast, downregulation of HSF2 seemed to increase the invasive properties, and HSF2 could therefore act as a tumor suppressor. In combination with bioinformatics analyses, these results were further validated in human pathology using tissue microarray and the molecular pathways behind these observations were elucidated by transcriptome analyses. Our results reveal involvement of two novel players in PrCa, HSF1 and HSF2 that intriguingly seem to have opposite roles in tumor invasion. We conclude that HSF1 and HSF2 have significant implications for the molecular understanding of cancer progression and invasion. Citation Format: Malin Akerfelt, Johanna Bjork, Tuomas Mirtti, Vidal Fey, Lea Sistonen, Matthias Nees. Opposing effects of heat shock factors 1 and 2 on prostate cancer invasion. [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 A46.