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Updated: Oct 18, 2025

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Chemotherapy of HER2- and MDM2-Enriched Breast Cancer Subtypes Induces Homologous Recombination DNA Repair and

Marcin Herok1,2, Bartosz Wawrzynow1,3, Marta J Maluszek1,3

  • 1International Institute of Molecular and Cell Biology in Warsaw, 02-109 Warsaw, Poland.

Cancers
|September 28, 2021
PubMed

Insights

MDM2 overexpression in HER2+ breast cancer reduces survival. Inhibiting MDM2 impairs DNA repair and chemoresistance, suggesting MDM2 as a therapeutic target for improving patient outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • MDM2 is implicated in cancer progression and drug resistance.
  • The role of MDM2 in DNA repair and its impact on chemotherapy response in HER2+ breast cancer requires further elucidation.

Purpose of the Study:

  • To investigate the role of MDM2 in HER2+ breast cancer survival and response to chemotherapy.
  • To explore the effect of MDM2 inhibition on DNA repair pathways and chemosensitization.

Main Methods:

  • Analysis of TCGA breast cancer database for MDM2 expression and patient survival.
  • In vitro studies using SKBR3 (HER2+) and H1299 (TP53-/-) cell lines.
  • Gene silencing of MDM2, drug treatment (doxorubicin, etoposide, camptothecin, neocarzinostatin), PARP inhibitor (olaparib), and assessment of DNA repair proteins (ATM, NBN, BRCA1) phosphorylation and protein-protein interactions.

Main Results:

  • MDM2 overexpression correlated with decreased survival in HER2+ breast cancer patients.
  • MDM2 inhibition reduced cancer cell survival and diminished homologous recombination (HR) DNA repair.
  • MDM2 inhibition sensitized cells to chemotherapy and PARP inhibitors.
  • MDM2's chaperone function is critical for HR DNA repair and chemoresistance acquisition.

Conclusions:

  • MDM2 plays a significant role in promoting chemoresistance in HER2+ breast cancer by facilitating HR DNA repair.
  • Targeting MDM2 could be a viable strategy to enhance chemotherapy efficacy and overcome drug resistance in this patient population.
Keywords:
DNA damage repairMDM2NBNchemoresistancehomologous recombination

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