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Updated: Jun 27, 2025

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Overcoming retinoic acid resistance in HER2-enriched breast cancers: role of MYC

Won-Shik Choi1, Rong-Zong Liu1, Caitlin Mak1

  • 1Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Canada.

The FEBS Journal
|May 6, 2024
PubMed

Insights

MYC causes resistance to retinoic acid (RA) in HER2-positive breast cancers by reducing CRABP2 levels. Depleting MYC or using RA with trastuzumab may improve treatment outcomes for specific patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • HER2-positive (HER2+) breast cancers overexpress HER2, often treated with trastuzumab.
  • Resistance to trastuzumab is a significant clinical challenge.
  • Retinoic acid (RA) shows promise for solid tumors, but HER2+ breast cancers are often RA-refractory.

Purpose of the Study:

  • Investigate the mechanism of RA resistance in HER2+ breast cancer.
  • Determine the role of MYC and CRABP2 in RA resistance.
  • Evaluate the potential of combining RA and trastuzumab therapy.

Main Methods:

  • Analysis of gene co-amplification (HER2 and RARA).
  • Assessment of MYC's role in regulating CRABP2 expression.
  • Evaluation of RA response following MYC depletion.
  • Testing combined RA and trastuzumab treatment efficacy.

Main Results:

  • MYC suppresses cellular retinoic acid binding protein 2 (CRABP2) expression, leading to RARα inactivation and RA resistance.
  • MYC depletion enhances RA responsiveness in HER2+ breast cancer cells.
  • RA treatment improves trastuzumab responsiveness.

Conclusions:

  • MYC is a key mediator of RA resistance in HER2+ breast cancer.
  • Targeting MYC or combining RA with trastuzumab may benefit patients with HER2-RARα co-amplified, low-MYC breast cancers.
Keywords:
HER2MYCbreast cancerretinoic acidtrastuzumab

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