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The F-Box Domain-Dependent Activity of EMI1 Regulates PARPi Sensitivity in Triple-Negative Breast Cancers

Antonio Marzio1, Joseph Puccini1, Youngho Kwon2

  • 1Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA; Perlmutter NYU Cancer Center, New York University School of Medicine, New York, NY 10016, USA.

Molecular Cell
|December 18, 2018
PubMed

Insights

EMI1 regulates PARPi sensitivity in triple-negative breast cancer (TNBC) by controlling RAD51 degradation. Restoring EMI1 levels re-sensitizes resistant TNBC cells to PARPi treatment.

Area of Science:

  • Molecular Oncology
  • Cancer Therapeutics
  • DNA Repair Mechanisms

Background:

  • The BRCA1-BRCA2-RAD51 axis is critical for homologous recombination repair (HRR), a pathway frequently impaired in breast cancers.
  • Poly (ADP-ribose) polymerase inhibitors (PARPis) are effective treatments for BRCA-mutated breast tumors, but resistance mechanisms limit their efficacy.

Purpose of the Study:

  • To identify novel modulators of PARPi sensitivity in triple-negative breast cancer (TNBC).
  • To elucidate the role of EMI1 in regulating RAD51 stability and HRR in the context of PARPi treatment.

Main Methods:

  • Conducted a genetic screen to identify factors influencing PARPi sensitivity in TNBC cells.
  • Investigated the interaction between EMI1, SCF ubiquitin ligase complex, and RAD51.
  • Analyzed protein levels in human breast cancer samples and evaluated EMI1 re-expression in cellular and mouse models.

Main Results:

  • Identified EMI1 as a key regulator of PARPi sensitivity, functioning through its F-box domain to promote RAD51 degradation.
  • Demonstrated that CHK1-mediated phosphorylation of RAD51 counteracts EMI1-dependent degradation, promoting HRR.
  • Observed an inverse correlation between EMI1 and RAD51 protein levels in human breast cancers and found that EMI1 downregulation confers PARPi resistance by restoring RAD51-dependent HRR.

Conclusions:

  • EMI1 acts as a crucial negative regulator of RAD51, impacting HRR and PARPi sensitivity in TNBC.
  • Downregulation of EMI1 is a mechanism of acquired resistance to PARPi in BRCA1-deficient TNBC.
  • Re-expression of EMI1 can overcome PARPi resistance, offering a potential therapeutic strategy for TNBC.
Keywords:
BRCA1CHK1DNA damageEMI1HRRPARPi resistanceRAD51breast cancerproteolysisubiquitin

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