Differential chromatin accessibility and transcriptional dynamics define breast cancer subtypes and their lineages
Michael D. Iglesia, Reyka G. Jayasinghe, Siqi Chen, Nadezhda V. Terekhanova, John M. Herndon, Erik Storrs, Alla Y. Karpova, Daniel Cui Zhou, Nataly Naser Al Deen, Andrew Shinkle, Rita Jui-Hsien Lu, Wagma Caravan, Andrew Houston, Yanyan Zhao, Kazuhito Sato, Preet Lal, Cherease Street, Fernanda Martins Rodrigues, Austin N. Southard-Smith, André Luiz N. Targino da Costa, Houxiang Zhu, Chia-Kuei Mo, Lisa Crowson, Robert S. Fulton, Matthew A. Wyczalkowski, Catrina C. Fronick, Lucinda A. Fulton, Hua Sun, Sherri R. Davies, Elizabeth L. Appelbaum, Sara E. Chasnoff, Madelyn Carmody, Candace Brooks, Ruiyang Liu, Michael C. Wendl, Clara Oh, Diane E. Bender, Carlos Cruchaga, Oscar Harari, Andrea Bredemeyer, Kory J. Lavine, Ron Bose, Julie A. Margenthaler, Jason M. Held, Samuel Achilefu, Foluso O. Ademuyiwa, Rebecca Aft, X. Cynthia, Graham A. Colditz, Tao Ju, Stephen T. Oh, James A. J. Fitzpatrick, E. Shelley Hwang, Kooresh I. Shoghi, Milan G. Chheda, Deborah V. Novack, Feng Chen, Ryan C. Fields, William E. Gillanders, Li Ding
Abstract
Abstract Breast cancer (BC) is defined by distinct molecular subtypes with different cells of origin. The transcriptional networks that characterize the subtype-specific tumor-normal lineages are not established. In this work, we applied bulk, single-cell and single-nucleus multi-omic techniques as well as spatial transcriptomics and multiplex imaging on 61 samples from 37 patients with BC to show characteristic links in gene expression and chromatin accessibility between BC subtypes and their putative cells of origin. Regulatory network analysis of transcription factors underscored the importance of BHLHE40 in luminal BC and luminal mature cells and KLF5 in basal-like tumors and luminal progenitor cells. Furthermore, we identify key genes defining the basal-like ( SOX6 and KCNQ3 ) and luminal A/B ( FAM155A and LRP1B ) lineages. Exhausted CTLA4-expressing CD8 + T cells were enriched in basal-like BC, suggesting an altered means of immune dysfunction. These findings demonstrate analysis of paired transcription and chromatin accessibility at the single-cell level is a powerful tool for investigating cancer lineage and highlight transcriptional networks that define basal and luminal BC lineages.