RF03 | PMON289 KLF4 drives estrogen driven tumor heterogeneity in breast cancer

Whilst hormonal therapies have proved effective in targeting ER positive breast cancer, intrinsic and acquired resistance to therapy has meant that the disease remains deadly. To identify potential drivers of transcriptional and epigenetic heterogeneity in breast cancer, we performed detailed single-cell multi-ome experiments +/- estrogen stimulation. Our results identified that the transcription factor KLF4 is highly associated with heterogeneity in our experimental models. KLF4 is one of four Yamanaka pluripotency factors that can reprogram cells to a stem like state and is also a pioneer factor, that possesses the ability to bind to condensed chromatin. Silencing of KLF4 significantly reduced transcriptional heterogeneity in multiple models. Importantly, we also found that KLF4 acts as a pioneer factor for ER. ER binding, transcriptional activity and chromatin accessibility at ER binding sites were lost upon KLF4 silencing. Using proteomics based interactome profiling, we find multiple other signaling pathway rely on KLF4. Together, our results suggest that KLF4 maintains plasticity in ER+ breast cancer cells and also functions as a pivotal factor for ER to function. Presentation: Saturday, June 11, 2022 1:36 p.m. - 1:41 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.