Abstract 1496: Understanding a novel interaction between HSF1 and ERRα in breast cancer

Breast Cancer is the most common type of cancer in women with 1 in 8 women being predicted to develop breast cancer during their lifetimes. Even after decades of ground-breaking research, new cases and deaths continue to rise. Oncogenesis can often be attributed to genetic alterations, which inadvertently lead to transcriptional dysregulation, often allowing them to successfully mitigate the effects of oxidative stress, metabolic stress, and others, ultimately giving them survival benefits. ERRα is an orphan nuclear receptor that regulates metabolic gene expression and has been linked to poor prognosis in many cancers, including that of the breast. Inhibiting ERRα has been identified as a potential therapeutic strategy but the underlying mechanism is not fully understood. HSF1, a master transcription regulator involved in heat shock response and protein homeostasis, has been implicated in oncogenesis and promotes cell proliferation and invasion. However, any interaction or cooperation between ERRα and HSF1 has not been investigated. Analyses of ChIP Seq data revealed a substantial number of overlapping binding peaks and shared target genes between HSF1 and ERRα. Gene ontology enrichment revealed these shared target genes are enriched for cellular pathways frequently dysregulated in cancer, such as cell proliferation. Using a novel ERRα transcriptional activity signature, it was observed that ERRα activity was strongly correlated with HSF1 activity in breast cancer patients. Furthermore, patients with high activities of both ERRα and HSF1 were found to have poorer prognosis. Since HSF1 and ERRα are transcription factors, we wanted to check for any cooperativity in their transcriptional activities. Luciferase-based reporter assays revealed ERRα enhanced HSF1 transcriptional activity. To further understand any interaction between ERRα and HSF1, we treated HEK293FT (non-cancer cell line) and HCC1937 (triple negative breast cancer cell line) with an ERRα inhibitor (XCT790) and an HSF1 inhibitor (DTHIB). We observed a reduction in HSF1 protein with ERRα inhibition and a reduction in ERRα with HSF1 inhibition. Moreover, co-immunoprecipitation assay results suggest a physical interaction between HSF1 and ERRα. Taken together, our data suggests a possible protein complex with HSF1 and ERRα that stabilizes both proteins and regulates genes supportive of breast tumor growth. Future studies will be looking at the role of this complex on oncogenesis and progression of breast cancer. These studies will lead to identification of probable therapeutic strategies exploiting this interaction. Citation Format: Sunandan Chakrabarti, Yuan Feng, David Adelfinsky, Jason Tennessen, Richard Carpenter. Understanding a novel interaction between HSF1 and ERRα in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1496.