p53-Mediated Senescence Impairs the Apoptotic Response to Chemotherapy and Clinical Outcome in Breast Cancer
Open accessAbstract
Studies on the role of TP53 mutation in breast cancer response to chemotherapy are conflicting. Here, we show that, contrary to dogma, MMTV-Wnt1 mammary tumors with mutant p53 exhibited a superior clinical response compared to tumors with wild-type p53. Doxorubicin-treated p53 mutant tumors failed to arrest proliferation, leading to abnormal mitoses and cell death, whereas p53 wild-type tumors arrested, avoiding mitotic catastrophe. Senescent tumor cells persisted, secreting senescence-associated cytokines exhibiting autocrine/paracrine activity and mitogenic potential. Wild-type p53 still mediated arrest and inhibited drug response even in the context of heterozygous p53 point mutations or absence of p21. Thus, we show that wild-type p53 activity hinders chemotherapy response and demonstrate the need to reassess the paradigm for p53 in cancer therapy.
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Partial induction of senescence in tumours could eradicate or exacerbate the tumours.
“The partial induction of senescence in tumours could eradicate or exacerbate the tumours 110,113”
From Inside and out: the activities of senescence in cancer (2014) · cites this paper as [110]
Senescent cells are resistant to apoptosis or mitotic catastrophe upon chemotherapy; if senescent tumour cells are not eliminated, sustained pro-tumorigenic cytokines can lead to worse outcome.
“Much like dormant cells, senescent cells are resistant to apoptosis or mitotic catastrophe upon chemotherapy, thus if senescent tumour cells are not eliminated, the sustained expression of pro-tumorigenic cytokines can lead to a worse outcome 110”
From Inside and out: the activities of senescence in cancer (2014) · cites this paper as [110]
Senescent cells have been postulated to mediate resistance to therapy and contribute to off-target systemic effects and cancer relapse after standard anticancer regimens.
“Senescent cells have also been postulated to mediate resistance to therapy, while contributing to off-target systemic effects and cancer relapse linked to the treatment with standard anticancer regimens.”
From Meta-hallmarks of aging and cancer (2023) · cites this paper as [199]
The efficacy of doxorubicin in the MMTV-PyMT breast cancer model is mitigated by eotaxin, CXCL5, and CCL5 released by residual senescent cancer cells.
“As an example, the efficacy of doxorubicin in the MMTV-PyMT breast cancer model is mitigated by eotaxin, CXCL5, and CCL5 released by residual senescent cancer cells.199”
From Meta-hallmarks of aging and cancer (2023) · cites this paper as [199]
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References 63 · Cited by 329
Research works printed but not linked: 2
- Collado M Gil J Efeyan A Guerra C Schuhmacher AJ Barradas M Benguria A Zaballos A Flores JM Barbacid M Tumour biology: senescence in premalignant tumours Nature 2005 436 642 16079833
- Mathieu MC Koscielny S Le Bihan ML Spielmann M Arriagada R p53 protein overexpression and chemosensitivity in breast cancer. Institut Gustave-Roussy Breast Cancer Group Lancet 1995 345 1182 7723572
- Authors
- Jackson, J. G., Pant, V., Li, Q., Chang, L. L., Quintás-Cardama, A., Garza, D., Tavana, O., Yang, P., Manshouri, T., Li, Y., El-Naggar, A. K., & Lozano, G.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Baylor College of Medicine (US)
- Corresponding author
- Lozano, Guillermina
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2012-06
- Volume
- 21
- Issue
- 6
- Pages
- 793-806
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC3376352
- OpenAlex
- W1964781873
- Cited by
- 329
- References
- 63
- Citations by year
- 2026: 8 · 2025: 15 · 2024: 25 · 2023: 22 · 2022: 30 · 2021: 20 · 2020: 23 · 2019: 25 · 2018: 24 · 2017: 19 · 2016: 21 · 2015: 30 · 2014: 28 · 2013: 26 · 2012: 13
- FWCI
- 15.34
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 447 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (CA34936, CA47296, CA82577, U01DE019765-01)
- National Cancer Institute (CA16672)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- p53, cellular senescence, breast cancer, chemotherapy response, doxorubicin, mitotic catastrophe, autocrine and paracrine signaling, p21, TP53 mutation, clinical outcomes
- MeSH terms
- Aging, Animals, Antibiotics, Antineoplastic, Breast Neoplasms, Doxorubicin, Humans, Mammary Tumor Virus, Mouse, Mammary Neoplasms, Experimental, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Blotting, Western, Gene Expression Regulation, Neoplastic, Tumor Suppressor Protein p53, Cytokines, Treatment Outcome, Apoptosis, Mice, Knockout, Reverse Transcriptase Polymerase Chain Reaction, RNA Interference, Cell Line, Tumor, Tumor Burden, Cyclin-Dependent Kinase Inhibitor p21, Wnt1 Protein, Mice
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