Single-Cell Transcriptomic Heterogeneity in Invasive Ductal and Lobular Breast Cancer Cells

Cancer Res. 2021 Jan 15;81(2):268-281. doi: 10.1158/0008-5472.CAN-20-0696. Epub 2020 Nov 4.


Invasive lobular breast carcinoma (ILC), one of the major breast cancer histologic subtypes, exhibits unique features compared with the well-studied ductal cancer subtype (IDC). The pathognomonic feature of ILC is loss of E-cadherin, mainly caused by inactivating mutations, but the contribution of this genetic alteration to ILC-specific molecular characteristics remains largely understudied. To profile these features transcriptionally, we conducted single-cell RNA sequencing on a panel of IDC and ILC cell lines, and an IDC cell line (T47D) with CRISPR-Cas9-mediated E-cadherin knockout (KO). Inspection of intracell line heterogeneity illustrated genetically and transcriptionally distinct subpopulations in multiple cell lines and highlighted rare populations of MCF7 cells highly expressing an apoptosis-related signature, positively correlated with a preadaptation signature to estrogen deprivation. Investigation of E-cadherin KO-induced alterations showed transcriptomic membranous systems remodeling, elevated resemblance to ILCs in regulon activation, and increased sensitivity to IFNγ-mediated growth inhibition via activation of IRF1. This study reveals single-cell transcriptional heterogeneity in breast cancer cell lines and provides a resource to identify drivers of cancer progression and drug resistance. SIGNIFICANCE: This study represents a key step towards understanding heterogeneity in cancer cell lines and the role of E-cadherin depletion in contributing to the molecular features of invasive lobular breast carcinoma.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD / genetics
  • Antigens, CD / metabolism
  • Biomarkers, Tumor / genetics*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology*
  • Cadherins / antagonists & inhibitors
  • Cadherins / genetics
  • Cadherins / metabolism
  • Carcinoma, Ductal, Breast / genetics
  • Carcinoma, Ductal, Breast / pathology*
  • Carcinoma, Lobular / genetics
  • Carcinoma, Lobular / pathology*
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Mutation
  • Prognosis
  • Single-Cell Analysis / methods*
  • Transcriptome*
  • Tumor Cells, Cultured


  • Antigens, CD
  • Biomarkers, Tumor
  • CDH1 protein, human
  • Cadherins