Somatic Cell Fusions Reveal Extensive Heterogeneity in Basal-like Breast Cancer

• The basal-like trait is generally dominant and defined by epigenetic mechanisms
• Common core epigenetic programs in luminal tumors are defined by FOXA1 super-enhancers
• Basal tumors show repression of luminal factors and high epigenetic heterogeneity
• Nuclear extracts or transcription factors can reprogram breast cancer cells

SummaryBasal-like and luminal breast tumors have distinct clinical behavior and molecular profiles, yet the underlying mechanisms are poorly defined. To interrogate processes that determine these distinct phenotypes and their inheritance pattern, we generated somatic cell fusions and performed integrated genetic and epigenetic (DNA methylation and chromatin) profiling. We found that the basal-like trait is generally dominant and is largely defined by epigenetic repression of luminal transcription factors. Definition of super-enhancers highlighted a core program common in luminal cells but a high degree of heterogeneity in basal-like breast cancers that correlates with clinical outcome. We also found that protein extracts of basal-like cells are sufficient to induce a luminal-to-basal phenotypic switch, implying a trigger of basal-like autoregulatory circuits. We determined that KDM6A might be required for luminal-basal fusions, and we identified EN1, TBX18, and TCF4 as candidate transcriptional regulators of the luminal-to-basal switch. Our findings highlight the remarkable epigenetic plasticity of breast cancer cells.

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