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Article

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

1
International Institute of Molecular and Cell Biology in Warsaw, 02-109 Warsaw, Poland
2
Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, Poland
3
Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 02-106 Warsaw, Poland
4
Center for Translational Medicine, Warsaw University of Life Sciences, 02-787 Warsaw, Poland
*
Author to whom correspondence should be addressed.
These authors contributed equally.
Present address: Foundation for Polish Science, 02-611 Warsaw, Poland.
Academic Editor: Dik C. van Gent
Cancers 2021, 13(18), 4501; https://doi.org/10.3390/cancers13184501
Received: 30 July 2021 / Revised: 28 August 2021 / Accepted: 1 September 2021 / Published: 7 September 2021
(This article belongs to the Collection DNA Damage in Cancer)
MDM2 is a protein responsible for negative regulation of the p53 tumor suppressor. In addition, MDM2 exhibits chaperone-like properties similar to the HSP90 molecular chaperone. Multiple studies revealed that MDM2 is deeply involved in cancer development and progression. Some recently published results indicate that the role of MDM2 in DNA repair inhibition is more complex than previously thought. We show that MDM2 is directly involved in the homologous recombination DNA repair, and its chaperone-like activity is crucial for this function. The DNA repair inhibition is a result of inefficient MDM2 dissociation from the NBN protein complex. When cancer cells are treated with chemotherapy, MDM2 can be easily released from the interaction and degraded, resulting in effective homologous recombination DNA repair, which translates into the acquisition of a chemoresistant phenotype by the tumor. This knowledge may allow for identification of the patients that are at particular risk of tumor 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 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. View Full-Text
Keywords: DNA damage repair; homologous recombination; MDM2; NBN; chemoresistance DNA damage repair; homologous recombination; MDM2; NBN; chemoresistance
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MDPI and ACS Style

Herok, M.; Wawrzynow, B.; Maluszek, M.J.; Olszewski, M.B.; Zylicz, A.; Zylicz, M. Chemotherapy of HER2- and MDM2-Enriched Breast Cancer Subtypes Induces Homologous Recombination DNA Repair and Chemoresistance. Cancers 2021, 13, 4501. https://doi.org/10.3390/cancers13184501

AMA Style

Herok M, Wawrzynow B, Maluszek MJ, Olszewski MB, Zylicz A, Zylicz M. Chemotherapy of HER2- and MDM2-Enriched Breast Cancer Subtypes Induces Homologous Recombination DNA Repair and Chemoresistance. Cancers. 2021; 13(18):4501. https://doi.org/10.3390/cancers13184501

Chicago/Turabian Style

Herok, Marcin, Bartosz Wawrzynow, Marta J. Maluszek, Maciej B. Olszewski, Alicja Zylicz, and Maciej Zylicz. 2021. "Chemotherapy of HER2- and MDM2-Enriched Breast Cancer Subtypes Induces Homologous Recombination DNA Repair and Chemoresistance" Cancers 13, no. 18: 4501. https://doi.org/10.3390/cancers13184501

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