Cited by 27Cancer-related Molecular PathwaysBreast Cancer Treatment StudiesPI3K/AKT/mTOR signaling in cancer

Effects of concomitant inactivation of p53 and pRb on response to doxorubicin treatment in breast cancer cell lines

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Huun, Johanna, Lønning, Per Eystein, Knappskog, Stian·2017·Cell Death Discovery

Abstract

Loss of TP53 and RB1 function have both been linked to poor response to DNA damaging drugs in breast cancer patients. We inactivated TP53 and/or RB1 by siRNA mediated knockdown in breast cancer cell lines varying with respect to ER/PgR and Her-2 status as well as TP53 and RB1 mutation status (MCF-7, T47D, HTB-122 and CRL2324) and determined effects on cell cycle arrest, apoptosis and senescence with or without concomitant treatment with doxorubicin. In T47D cells, we found the cell cycle phase distribution to be altered when inactivating TP53 (P=0.0003) or TP53 and RB1 concomitantly (P≤0.001). No similar changes were observed in MCF-7, HTB-122 or CRL2324 cells. While no significant change was observed for the CRL2324 cells upon doxorubicin treatment, MCF-7, T47D as well as HTB-122 cells responded to knockdown of TP53 and RB1 in concert, with a decrease in the fraction of cells in G1/G0-phase (P=0.042, 0.021 and 0.027, respectively). Inactivation of TP53 and/or RB1 caused no change in induction of apoptosis. Upon doxorubicin treatment, inactivation of TP53 or RB1 separately caused no induction of apoptosis in MCF-7 and HTB-122 cells; however, concomitant inactivation leads to a slightly reduced activation of apoptosis. Interestingly, upon doxorubicin treatment, concomitant inactivation of TP53 and RB1 caused a decrease in senescence in MCF-7 cells (P=0.027). Comparing the effects of concomitant knockdown on apoptosis and senescence, we observed a strong interaction (P=0.001). We found concomitant inactivation of TP53 and RB1 to affect various routes of response to doxorubicin treatment in breast cancer cells.

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Crossref · 10.1038/cddiscovery.2017.26

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  • Mitotic catastrophe is a major mechanism of action of anticancer chemotherapeutics, reflecting increased resistance of neoplastic cells to intrinsic apoptosis.

    “However, mitotic catastrophe appears to constitute a major mechanism of action of anticancer chemotherapeutics, mostly reflecting the increased resistance of neoplastic cells to the induction of intrinsic apoptosis [1004–1009].”

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Authors
Huun, J., Lønning, P. E., & Knappskog, S.
Affiliations
  • University of Bergen (NO)
  • Haukeland University Hospital (NO)
Corresponding author
Knappskog, Stian
Venue
Cell Death Discovery
Published
2017-05-22
Volume
3
Issue
1
Pages
17026-17026
ISSN
2058-7716 (ISSN-L)
OpenAlex
W2617381402
Cited by
27
References
38
Citations by year
2026: 1 · 2024: 1 · 2023: 2 · 2022: 2 · 2021: 5 · 2020: 5 · 2019: 3 · 2018: 7 · 2017: 1
FWCI
1.93
Type
journal article
Language
en
Open access
Locations
  • Cell Death Discovery (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Kreftforeningen
  • Bergens Forskningsstiftelse
Topics
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Keywords
TP53, RB1, p53 inactivation, doxorubicin, breast cancer, chemoresistance, cell cycle arrest, apoptosis, senescence, siRNA knockdown, MCF-7 cells, T47D cells, HER2 status, estrogen receptor, progesterone receptor, TP53 mutation

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