Effects of concomitant inactivation of p53 and pRb on response to doxorubicin treatment in breast cancer cell lines
Open accessAbstract
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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
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].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [1004]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Integrative Genomic Profiling of Human Prostate Cancer
Taylor, B. S., Schultz, N. D., Hieronymus, H., Gopalan, A., Xiao, Y., Carver, B. S., Arora, V. K., Kaushik, P., Cerami, E. G., Reva, B. A., et al. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.05.026 · Cited by 3,653 · see citing works
A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes
Neve, R. M., Chin, K., Fridlyand, J., Yeh, J., Baehner, F. L., Fevr, T., Clark, L., Bayani, N., Coppé, J., Tong, F. K., et al. (2006) · Cancer Cell · doi:10.1016/j.ccr.2006.10.008 · Cited by 3,191 · see citing works
Live or let die: the cell's response to p53
Vousden, K. H., & Lü, X. (2002) · Nature reviews. Cancer · doi:10.1038/nrc864 · Cited by 3,177 · see citing works
The mutational landscape of lethal castration-resistant prostate cancer
Grasso, C. S., Wu, Y.-M., Robinson, D. R., Cao, X., Dhanasekaran, S. M., Khan, A. P., Quist, M. J., Jing, X., Lonigro, R. J., Brenner, J. C., et al. (2012) · Nature · doi:10.1038/nature11125 · Cited by 2,517 · see citing works
Gewirtz, D. (1999) · Biochemical Pharmacology · doi:10.1016/s0006-2952(98)00307-4 · Cited by 2,242 · see citing works
Restoration of p53 function leads to tumour regression in vivo
Ventura, A., Kirsch, D. G., McLaughlin, M. E., Tuveson, D. A., Grimm, J., Lintault, L., Newman, J., Reczek, E. E., Weissleder, R., & Jacks, T. (2007) · Nature · doi:10.1038/nature05541 · Cited by 1,820 · see citing works
Di Leonardo, A., Linke, S. P., Clarkin, K., & Wahl, G. M. (1994) · Genes & Development · doi:10.1101/gad.8.21.2540 · Cited by 1,215 · see citing works
A Senescence Program Controlled by p53 and p16INK4a Contributes to the Outcome of Cancer Therapy
Schmitt, C. A., Fridman, J. S., Yang, M., Lee, S., Baranov, E., Hoffman, R. M., & Lowe, S. W. (2002) · Cell · doi:10.1016/s0092-8674(02)00734-1 · Cited by 1,050 · see citing works
Cellular mechanisms of tumour suppression by the retinoblastoma gene
Burkhart, D. L., & Sage, J. (2008) · Nature Reviews Cancer · doi:10.1038/nrc2399 · Cited by 974 · see citing works
Kao, J., Salari, K., Bocanegra, M., Choi, Y.-L., Girard, L., Gandhi, J., Kwei, K. A., Hernandez-Boussard, T., Wang, P., Gazdar, A. F., et al. (2009) · PLoS ONE · doi:10.1371/journal.pone.0006146 · Cited by 788 · see citing works
Apoptosis, p53, and tumor cell sensitivity to anticancer agents.
Brown, J. M., & Wouters, B. G. (1999) · PubMed · Cited by 696 · see citing works
TP53 Mutation and Survival in Chronic Lymphocytic Leukemia
Zenz, T., Eichhorst, B. F., Busch, R. M., Denzel, T., Häbe, S., Winkler, D. F. H., Bühler, A., Edelmann, J., Bergmann, M., Hopfinger, G., et al. (2010) · Journal of Clinical Oncology · doi:10.1200/jco.2009.27.8762 · Cited by 617 · see citing works
Molecular Stratification of Triple-Negative Breast Cancers
Perou, C. M. (2011) · The Oncologist · doi:10.1634/theoncologist.2011-s1-61 · Cited by 582 · see citing works
Distinct p53 Transcriptional Programs Dictate Acute DNA-Damage Responses and Tumor Suppression
Brady, C. A., Jiang, D., Mello, S. S., Johnson, T. M., Jarvis, L. A., Kozak, M. M., Broz, D. K., Basak, S., Park, E. J., McLaughlin, M. E., et al. (2011) · Cell · doi:10.1016/j.cell.2011.03.035 · Cited by 533 · see citing works
Structural Rearrangement of the Retinoblastoma Gene in Human Breast Carcinoma
Tang, A., Varley, J. M., Chakraborty, S., Murphree, A. L., & Fung, Y.-K. T. (1988) · Science · doi:10.1126/science.3175651 · Cited by 403 · see citing works
Chk2 kinase — a busy messenger
Bártek, J., Falck, J., & Lukas, J. (2001) · Nature Reviews Molecular Cell Biology · doi:10.1038/35103059 · Cited by 400 · see citing works
Tailoring to RB: tumour suppressor status and therapeutic response
Knudsen, E. S., & Knudsen, K. E. (2008) · Nature reviews. Cancer · doi:10.1038/nrc2401 · Cited by 345 · see citing works
Geisler, S. B., Lønning, P. E., Aas, T., Johnsen, H., Fluge, Ø., Haugen, D. F., Lillehaug, J. R., Akslen, L. A., & Børresen‐Dale, A. (2001) · PubMed · Cited by 326 · see citing works
Self-citationCellular responses to DNA damage: cell-cycle checkpoints, apoptosis and the roles of p53 and ATM.
Enoch, T., & Norbury, C. (1995) · Trends in Biochemical Sciences · doi:10.1016/s0968-0004(00)89093-3 · Cited by 261 · see citing works
pRB plays an essential role in cell cycle arrest induced by DNA damage
Harrington, E. A., Bruce, J. L., Harlow, E., & Dyson, N. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.20.11945 · Cited by 242 · see citing works
The Petinoblastoma Tumor Suppressor Protein
Wang, J. Y. J., Knudson, E. S., & Welch, P. J. (1994) · Advances in cancer research · doi:10.1016/s0065-230x(08)60834-9 · Cited by 220 · see citing works
Molecular Stratification of Triple-Negative Breast Cancers
Perou, C. M. (2010) · The Oncologist · doi:10.1634/theoncologist.2010-s5-39 · Cited by 203 · see citing works
Lüpertz, R., Wätjen, W., Kahl, R., & Chovolou, Y. (2010) · Toxicology · doi:10.1016/j.tox.2010.03.012 · Cited by 197 · see citing works
Induction of senescence with doxorubicin leads to increased genomic instability of HCT116 cells
Śliwińska, M. A., Mosieniak, G., Wolanin, K., Babik, A., Piwocka, K., Magalska, A., Szczepanowska, J., Fronk, J., & Sikora, E. (2008) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2008.04.011 · Cited by 179 · see citing works
Geisler, S. B., Børresen‐Dale, A., Johnsen, H., et al. (2003) · PubMed · Cited by 155 · see citing works
Laine, A., Sihto, H., Come, C., Rosenfeldt, M. T., Zwolinska, A., Niemelä, M., Khanna, A., Chan, E. K., Kähäri, V.-M., Kellokumpu-Lehtinen, P.-L., et al. (2013) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0292 · Cited by 130 · see citing works
Doxorubicin Exerts Cytotoxic Effects through Cell Cycle Arrest and Fas-Mediated Cell Death
Kim, H., Lee, Y., & Kim, D. (2009) · Pharmacology · doi:10.1159/000245937 · Cited by 127 · see citing works
Thirteen new p53 gene mutants identified among 41 human breast cancer cell lines
Wasielewski, M., Elstrodt, F., Klijn, J. G. M., et al. (2006) · Breast Cancer Research and Treatment · doi:10.1007/s10549-006-9186-z · Cited by 110 · see citing works
Immortalization of oral keratinocytes by functional inactivation of the p53 and pRb pathways
Smeets, S. J., van der Plas, M., Schaaij‐Visser, T. B. M., van Veen, E. A. M., van Meerloo, J., Braakhuis, B. J. M., Steenbergen, R. D. M., & Brakenhoff, R. H. (2010) · International Journal of Cancer · doi:10.1002/ijc.25474 · Cited by 104 · see citing works
Chrisanthar, R., Knappskog, S., Løkkevik, E., Anker, G. B., Østenstad, B., Lundgren, S., Berge, E. O., Risberg, T., Mjaaland, I., Mæhle, L., et al. (2008) · PLoS ONE · doi:10.1371/journal.pone.0003062 · Cited by 94 · see citing works
Self-citationPreudhomme, C., Dervite, I., Wattel, E., Vanrumbeke, M., FLACTIF, M., Laı̈, J. L., Hecquet, B., Copin, M., Nelken, B., & Gosselin, B. J. (1995) · Journal of Clinical Oncology · doi:10.1200/jco.1995.13.4.812 · Cited by 81 · see citing works
Witkiewicz, A. K., Ertel, A., McFalls, J. M., Valsecchi, M. E., Schwartz, G. F., & Knudsen, E. S. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-0903 · Cited by 70 · see citing works
Genes causing inherited cancer as beacons to identify the mechanisms of chemoresistance
Lønning, P. E. (2004) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2004.01.005 · Cited by 54 · see citing works
Self-citationLønning, P. E., & Knappskog, S. (2013) · Oncogene · doi:10.1038/onc.2013.48 · Cited by 53 · see citing works
Self-citationAntitumor mechanisms when pRb and p53 are genetically inactivated
Zhu, L., Lu, Z., & Zhao, H.-T. (2014) · Oncogene · doi:10.1038/onc.2014.399 · Cited by 47 · see citing works
Berge, E. O., Knappskog, S., Geisler, S. B., Staalesen, V., Pacal, M., Børresen‐Dale, A., Puntervoll, P., Lillehaug, J. R., & Lønning, P. E. (2010) · Molecular Cancer · doi:10.1186/1476-4598-9-173 · Cited by 32 · see citing works
Self-citationKnappskog, S., Berge, E. O., Chrisanthar, R., et al. (2015) · Molecular Oncology · doi:10.1016/j.molonc.2015.04.008 · Cited by 24 · see citing works
Self-citationAlterations of the retinoblastoma gene in metastatic breast cancer
Berge, E. O., Knappskog, S., Lillehaug, J. R., et al. (2011) · Clinical & Experimental Metastasis · doi:10.1007/s10585-011-9375-y · Cited by 18 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Galluzzi, L., Vitale, I., Aaronson, S. A., Abrams, J. M., Adam, D., Agostinis, P., Alnemri, E. S., Altucci, L., Amelio, I., Andrews, D. W., et al. (2018) · Cell Death & Differentiation · doi:10.1038/s41418-017-0012-4 · Cited by 6,680 · see citing works
- 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)
- PMC
- PMC5439126
- 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
- gold
- doi.org
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review