Heterogeneity within molecular subtypes of breast cancer

Am J Physiol Cell Physiol. 2021 Aug 1;321(2):C343-C354. doi: 10.1152/ajpcell.00109.2021. Epub 2021 Jun 30.


Breast cancer is the quintessential example of how molecular characterization of tumor biology guides therapeutic decisions. From the discovery of the estrogen receptor to current clinical molecular profiles to evolving single-cell analytics, the characterization and compartmentalization of breast cancer into divergent subtypes is clear. However, competing with this divergent model of breast cancer is the recognition of intratumoral heterogeneity, which acknowledges the possibility that multiple different subtypes exist within a single tumor. Intratumoral heterogeneity is driven by both intrinsic effects of the tumor cells themselves as well as extrinsic effects from the surrounding microenvironment. There is emerging evidence that these intratumoral molecular subtypes are not static; rather, plasticity between divergent subtypes is possible. Interconversion between seemingly different subtypes within a tumor drives tumor progression, metastases, and treatment resistance. Therapeutic strategies must, therefore, contend with changing phenotypes in an individual patient's tumor. Identifying targetable drivers of molecular heterogeneity may improve treatment durability and disease progression.

Keywords: cell-state heterogeneity; dynamic interconversion; hierarchical heterogeneity; intratumoral heterogeneity; plasticity.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Biomarkers, Tumor / genetics*
  • Breast Neoplasms / diagnosis
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology*
  • Humans
  • Prognosis
  • Receptors, Estrogen / genetics
  • Receptors, Estrogen / metabolism*
  • Single-Cell Analysis / methods
  • Tumor Microenvironment* / physiology


  • Biomarkers, Tumor
  • Receptors, Estrogen