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

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

Analyzing the TCGA breast cancer database, we discovered that patients with the HER2 cancer subtype and overexpression of MDM2 exhibited decreased post-treatment survival. Inhibition of MDM2 expression in the SKBR3 cell line (HER2 subtype) diminished the survival of cancer cells treated with doxorub...

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Bibliographic Details
Published in:Cancers Vol. 13; no. 18; p. 4501
Main Authors: Herok, Marcin, Wawrzynow, Bartosz, Maluszek, Marta J., Olszewski, Maciej B., Zylicz, Alicja, Zylicz, Maciej
Format: Journal Article
Language:English
Published: Basel MDPI AG 07-09-2021
MDPI
Subjects:
Antibodies
Apoptosis
BRCA1 protein
Breast cancer
Camptothecin
Cancer therapies
Cell culture
Cell cycle
Cell growth
Chemoresistance
Chemotherapy
Deoxyribonucleic acid
DNA
DNA damage
DNA repair
Doxorubicin
ErbB-2 protein
Etoposide
Gene expression
Genomes
Homologous recombination
Hsp90 protein
Kinases
MDM2 protein
Mutation
p53 Protein
Patients
Phenotypes
Phosphorylation
Poly(ADP-ribose) polymerase
Proteins
Software
Survival analysis
Transcription factors
Tumor suppressor genes
United States > US
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Summary:Analyzing the TCGA breast cancer database, we discovered that patients with the HER2 cancer subtype and overexpression of MDM2 exhibited decreased post-treatment survival. Inhibition of MDM2 expression in the SKBR3 cell line (HER2 subtype) diminished the survival of cancer cells treated with doxorubicin, etoposide, and camptothecin. Moreover, we demonstrated that inhibition of MDM2 expression diminished DNA repair by homologous recombination (HR) and sensitized SKBR3 cells to a PARP inhibitor, olaparib. In H1299 (TP53−/−) cells treated with neocarzinostatin (NCS), overexpression of MDM2 WT or E3-dead MDM2 C478S variant stimulated the NCS-dependent phosphorylation of ATM, NBN, and BRCA1, proteins involved in HR DNA repair. However, overexpression of chaperone-dead MDM2 K454A variant diminished phosphorylation of these proteins as well as the HR DNA repair. Moreover, we demonstrated that, upon NCS treatment, MDM2 K454A interacted with NBN more efficiently than MDM2 WT and that MDM2 WT was degraded more efficiently than MDM2 K454A. Using a proliferation assay, we showed that overexpression of MDM2 WT, but not MDM2 K454A, led to acquisition of resistance to NCS. The presented results indicate that, following chemotherapy, MDM2 WT was released from MDM2-NBN complex and efficiently degraded, hence allowing extensive HR DNA repair leading to the acquisition of chemoresistance by cancer cells.
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These authors contributed equally.
Present address: Foundation for Polish Science, 02-611 Warsaw, Poland.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers13184501