Bioelectric and Epigenetic Landscapes in Lateralized Breast Tumors Reveal Distinct Tumor Microenvironment Signatures

Cell communication within the tumor microenvironment (TME) plays a pivotal role in cancer progression. We report that breast tumors arising in the left (L) versus right (R) mammary glands exhibit asymmetry in composition, bioelectric state, and epigenetic regulation, suggesting a lateralized TME shaped by differential cell communication. TCGA analysis of invasive ductal carcinomas revealed that R-tumors have higher stromal content, enriched in cancer-associated fibroblasts (CAFs), particularly inflammatory CAFs, while L-tumors are enriched in dividing CAFs. These differences were confirmed in paired L-R xenografts, where R-tumors showed increased α-SMA. In vitro, L-sided tissue extracts induced greater membrane depolarization in cancer cells, a pattern also observed in xenografts. Methylome profiling showed that L-tumors are hypermethylated at ion channel genes—especially connexins—correlating with reduced expression. A computational model demonstrated that bistable states of membrane potential and methylation can spontaneously emerge based on initial conditions and gap junction coupling strength. These results reveal that L-R asymmetry is an overlooked layer of tumor heterogeneity, with potential implications for understanding cancer biology and designing spatially informed therapies.