Single-cell transcriptomics reveals involution mimicry during the specification of the basal breast cancer subtype
Fátima Valdés‐Mora, Robert Salomon, Brian Gloss, Andrew Man Kit Law, Jeron Venhuizen, Lesley Castillo, Kendelle J. Murphy, Astrid Magenau, Michael Papanicolaou, Laura Rodríguez de la Fuente, Daniel Roden, Yolanda Colino‐Sanguino, Zoya Kikhtyak, Nona Farbehi, James R. W. Conway, Neblina Sikta, Samantha R. Oakes, Thomas R. Cox, Sean O’Donoghue, Paul Timpson, Christopher J. Ormandy, David Gallego‐Ortega
Abstract
Basal breast cancer is associated with younger age, early relapse, and a high mortality rate. Here, we use unbiased droplet-based single-cell RNA sequencing (RNA-seq) to elucidate the cellular basis of tumor progression during the specification of the basal breast cancer subtype from the luminal progenitor population in the MMTV-PyMT (mouse mammary tumor virus-polyoma middle tumor-antigen) mammary tumor model. We find that basal-like cancer cells resemble the alveolar lineage that is specified upon pregnancy and encompass the acquisition of an aberrant post-lactation developmental program of involution that triggers remodeling of the tumor microenvironment and metastatic dissemination. This involution mimicry is characterized by a highly interactive multicellular network, with involution cancer-associated fibroblasts playing a pivotal role in extracellular matrix remodeling and immunosuppression. Our results may partially explain the increased risk and poor prognosis of breast cancer associated with childbirth.