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

Cell Rep. 2021 Apr 13;35(2):108945. doi: 10.1016/j.celrep.2021.108945.


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.

Keywords: Elf5; alveolar lineage; basal breast cancer; cancer-associated fibroblast; involution; mammary gland epithelial hierarchy; pregnancy-associated breast cancer; scRNA-seq.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cancer-Associated Fibroblasts / metabolism*
  • Cancer-Associated Fibroblasts / pathology
  • Carcinoma, Basal Cell / genetics*
  • Carcinoma, Basal Cell / metabolism
  • Carcinoma, Basal Cell / pathology
  • Cell Lineage / genetics
  • Chemokine CXCL12 / genetics
  • Chemokine CXCL12 / metabolism
  • Collagen Type I, alpha 1 Chain / genetics
  • Collagen Type I, alpha 1 Chain / metabolism
  • Extracellular Matrix / metabolism
  • Extracellular Matrix / pathology
  • Female
  • Gene Expression Regulation, Neoplastic
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Mammary Glands, Animal / metabolism*
  • Mammary Glands, Animal / pathology
  • Mammary Glands, Animal / virology
  • Mammary Neoplasms, Animal / genetics*
  • Mammary Neoplasms, Animal / metabolism
  • Mammary Neoplasms, Animal / pathology
  • Mammary Tumor Virus, Mouse / growth & development
  • Mammary Tumor Virus, Mouse / pathogenicity
  • Matrix Metalloproteinase 3 / genetics
  • Matrix Metalloproteinase 3 / metabolism
  • Mice
  • Neoplasm Metastasis
  • Pregnancy
  • Single-Cell Analysis
  • Transcriptome*
  • Tumor Microenvironment / genetics


  • Chemokine CXCL12
  • Col1a1 protein, mouse
  • Collagen Type I, alpha 1 Chain
  • Cxcl12 protein, mouse
  • Matrix Metalloproteinase 3
  • Mmp3 protein, mouse