Mismatch repair deficiency predicts response to HER2 blockade in HER2-negative breast cancer

Nat Commun. 2021 May 19;12(1):2940. doi: 10.1038/s41467-021-23271-0.


Resistance to endocrine treatment occurs in ~30% of ER+ breast cancer patients resulting in ~40,000 deaths/year in the USA. Preclinical studies strongly implicate activation of growth factor receptor, HER2 in endocrine treatment resistance. However, clinical trials of pan-HER inhibitors in ER+/HER2- patients have disappointed, likely due to a lack of predictive biomarkers. Here we demonstrate that loss of mismatch repair activates HER2 after endocrine treatment in ER+/HER2- breast cancer cells by protecting HER2 from protein trafficking. Additionally, HER2 activation is indispensable for endocrine treatment resistance in MutL- cells. Consequently, inhibiting HER2 restores sensitivity to endocrine treatment. Patient data from multiple clinical datasets supports an association between MutL loss, HER2 upregulation, and sensitivity to HER inhibitors in ER+/HER2- patients. These results provide strong rationale for MutL loss as a first-in-class predictive marker of sensitivity to combinatorial treatment with endocrine intervention and HER inhibitors in endocrine treatment-resistant ER+/HER2- breast cancer patients.

Trial registration: ClinicalTrials.gov NCT00265759.

Publication types

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

MeSH terms

  • Animals
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Cell Line, Tumor
  • DNA Mismatch Repair* / drug effects
  • DNA Mismatch Repair* / genetics
  • Drug Resistance, Neoplasm / genetics
  • Female
  • Gene Knockdown Techniques
  • Humans
  • MCF-7 Cells
  • Mice
  • Mice, Nude
  • Mice, SCID
  • MutL Protein Homolog 1 / genetics
  • MutL Protein Homolog 1 / metabolism
  • MutL Proteins / genetics
  • MutL Proteins / metabolism
  • Proteins / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptor, ErbB-2 / antagonists & inhibitors*
  • Receptor, ErbB-2 / genetics
  • Receptor, ErbB-2 / metabolism*
  • Receptors, Estrogen / metabolism
  • Signal Transduction
  • Xenograft Model Antitumor Assays


  • MLH1 protein, human
  • Proteins
  • RNA, Messenger
  • Receptors, Estrogen
  • lysosomal proteins
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • MutL Protein Homolog 1
  • MutL Proteins

Associated data

  • ClinicalTrials.gov/NCT00265759