ArticleMolecular oncology2015
Concomitant inactivation of the p53- and pRB- functional pathways predicts resistance to DNA damaging drugs in breast cancer in vivo.
Article in Molecular oncology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 24 citations in OpenAlex.
- Trial
- TP53 inhibitor PFTα increases the sensitivity of arsenic trioxide in TP53 wildtype tumor cells.FEBS open bio · 2022Article
- Atypical responses to neoadjuvant chemotherapy combined with accelerated partial breast tumor-directed radiotherapy: two cases and considerations for future clinical trials.Reports of practical oncology and radiotherapy : journal of Greatpoland Cancer Center in Poznan and Polish Society of Radiation Oncology · 2022Article
- Inflammatory Breast Cancer: Clinical Implications of Genomic Alterations and Mutational Profiling.Cancers · 2020Article
- Differences in prognosis by p53 expression after neoadjuvant chemotherapy in triple-negative breast cancer.Annals of surgical treatment and research · 2020Article
- Chemoresistance‑related long non‑coding RNA expression profiles in human breast cancer cells.Molecular medicine reports · 2018Article
- Molecular targeting of the Aurora-A/SMAD5 oncogenic axis restores chemosensitivity in human breast cancer cells.Oncotarget · 2017Article
- TP53 Mutations in Breast and Ovarian Cancer.Cold Spring Harbor perspectives in medicine · 2017Review
- Effects of concomitant inactivation of p53 and pRb on response to doxorubicin treatment in breast cancer cell lines.Cell death discovery · 2017Article
- Heterogeneous perivascular cell coverage affects breast cancer metastasis and response to chemotherapy.JCI insight · 2016Article
- 11a-N-Tosyl-5-deoxi-pterocarpan, LQB-223, a novel compound with potent antineoplastic activity toward breast cancer cells with different phenotypes.Journal of cancer research and clinical oncology · 2016Article
- Dual function of MDM2 and MDMX toward the tumor suppressors p53 and RB.Genes & cancer · 2016Review
- Prevalence of theHereditary cancer in clinical practice · 2016Article
- Concomitant inactivation of the p53- and pRB- functional pathways predicts resistance to DNA damaging drugs in breast cancer in vivo.Molecular oncology · 2015Article
Corrections and comments
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Authors and funding
19 authors at 7 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Chemoresistance is the main obstacle to cancer cure. Contrasting studies focusing on single gene mutations, we hypothesize chemoresistance to be due to inactivation of key pathways affecting cellular mechanisms such as apoptosis, senescence, or DNA repair. In support of this hypothesis, we have previously shown inactivation of either TP53 or its key activators CHK2 and ATM to predict resistance to DNA damaging drugs in breast cancer better than TP53 mutations alone. Further, we hypothesized that redundant pathway(s) may compensate for loss of p53-pathway signaling and that these are inactivated as well in resistant tumour cells. Here, we assessed genetic alterations of the retinoblastoma gene (RB1) and its key regulators: Cyclin D and E as well as their inhibitors p16 and p27. In an exploratory cohort of 69 patients selected from two prospective studies treated with either doxorubicin monotherapy or 5-FU and mitomycin for locally advanced breast cancers, we found defects in the pRB-pathway to be associated with therapy resistance (p-values ranging from 0.001 to 0.094, depending on the cut-off value applied to p27 expression levels). Although statistically weaker, we observed confirmatory associations in a validation cohort from another prospective study (n = 107 patients treated with neoadjuvant epirubicin monotherapy; p-values ranging from 7.0 × 10(-4) to 0.001 in the combined data sets). Importantly, inactivation of the p53-and the pRB-pathways in concert predicted resistance to therapy more strongly than each of the two pathways assessed individually (exploratory cohort: p-values ranging from 3.9 × 10(-6) to 7.5 × 10(-3) depending on cut-off values applied to ATM and p27 mRNA expression levels). Again, similar findings were confirmed in the validation cohort, with p-values ranging from 6.0 × 10(-7) to 6.5 × 10(-5) in the combined data sets. Our findings strongly indicate that concomitant inactivation of the p53- and pRB- pathways predict resistance towards anthracyclines and mitomycin in breast cancer in vivo.
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