Single-cell transcriptomics reveals involution mimicry during the specification of the basal breast cancer subtype

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. [Display omitted] •Drop-seq reveals a strong cancer cell heterogeneity in PyMT mammary tumors•Elf5 redefines cancer cell states toward basal-like with pro-metastatic features•PyMT/Elf5 tumors show cellular and molecular characteristics of involution mimicry•Involution CAFs in PyMT/Elf5 tumors interconnect the TME and cancer cells Using single-cell transcriptomics, Valdés-Mora et al. show that Elf5 drives alveolar lineage differentiation in PyMT tumors, resulting in cancer cell states with basal-like characteristics and a multicellular process of unresolved lactation, with concomitant acquisition of metastasis. This study may partially explain the poor prognosis of breast cancer associated with childbirth.