Alterations in the p53 isoform ratio govern breast cancer cell fate in response to DNA damage

Reinhardt, Luiza Steffens; Zhang, Xiajie; Groen, Kira; Morten, Brianna C.; Iuliis, Geoffry N. De; Braithwaite, Antony W.; Bourdon, Jean-Christophe; Avery‐Kiejda, Kelly A.

doi:10.1038/s41419-022-05349-9

Cited by 11 publications

(45 citation statements)

References 78 publications

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“…The cancer-promoting functions of Δ40p53 are less thoroughly characterized. However, in response to DNA damage, Δ40p53 inhibited apoptosis [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

Increased Expression of the Δ133p53β Isoform Enhances Brain Metastasis

Jesus

Taha

Wang

et al. 2023

IJMS

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The Δ133p53β isoform is increased in many primary tumors and has many tumor-promoting properties that contribute to increased proliferation, migration and inflammation. Here we investigated whether Δ133p53β contributed to some of the most aggressive tumors that had metastasized to the brain. Δ133p53β mRNA expression was measured in lung, breast, melanoma, colorectal metastases and, where available, the matched primary tumor. The presence of Δ133p53β expression was associated with the time for the primary tumor to metastasize and overall survival once the tumor was detected in the brain. Δ133p53β was present in over 50% of lung, breast, melanoma and colorectal metastases to the brain. It was also increased in the brain metastases compared with the matched primary tumor. Brain metastases with Δ133p53β expressed were associated with a reduced time for the primary tumor to metastasize to the brain compared with tumors with no Δ133p53β expression. In-vitro-based analyses in Δ133p53β-expressing cells showed increased cancer-promoting proteins on the cell surface and increased downstream p-AKT and p-MAPK signaling. Δ133p53β-expressing cells also invaded more readily across a mock blood–brain barrier. Together these data suggested that Δ133p53β contributes to brain metastases by making cells more likely to invade the brain.

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“…The cancer-promoting functions of Δ40p53 are less thoroughly characterized. However, in response to DNA damage, Δ40p53 inhibited apoptosis [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

Increased Expression of the Δ133p53β Isoform Enhances Brain Metastasis

Jesus

Taha

Wang

et al. 2023

IJMS

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“…Δ40p53 or p53 antibodies were co-stained with antibodies that detect transcription factors that regulate stem cells (Nanog, Sox2, or Oct4). Δ40p53, which we have previously shown to localise in both the nucleus and cytoplasm in these cells (20), colocalised with Nanog, Sox2, and Oct4 (which are localised mainly in the nucleoplasm) in both breast cancer cell lines (Fig. 2A, B) (p < 0.05 for Nanog, Sox2, and Oct4 in MCF-7 and Nanog in ZR75-1).…”

Section: High Levels Of δ40p53 Induce Stem Cell Marker Expressionmentioning

confidence: 57%

“…We have demonstrated that high levels of the Δ40p53 isoform supress cellular mobility and proliferation (18), however, following doxorubicin (DOX), a high Δ40p53:p53 ratio impairs the canonical p53 DNA damage response (20). In support of this, a study from our group has shown that Δ40p53 is potentially associated with cisplatin response in melanoma (21).…”

Section: Introductionmentioning

confidence: 91%

“…Given that p53 inactivation disrupts this balance and promotes pluripotency and somatic cell reprogramming, we next explored the association of Δ40p53 with cell pluripotency by using MCF-7 sublines in which Δ40p53 has been stably knocked down (-shΔ40p53) or overexpressed (Δ40p53) (18). In the Δ40p53 overexpression cells, we have previously observed increased expression and stability of p53, in spite of that, these cells show a high Δ40p53:p53 ratio (20). An empty vector (LeGO), a nontargeting control shRNA (-shNT), and a full-length transactivation p53 knockdown (-shp53) subline were also used (18).…”

Section: High Levels Of δ40p53 Induce Stem Cell Marker Expressionmentioning

confidence: 99%

“…In a cancer context, increased levels of Δ40p53 were detected in glioblastoma, but not in the cerebral cortex, which is predominantly composed of differentiated cells, moreover, its expression pro le in glioblastoma xenografts resembled highly proliferative and undifferentiated stem cells (24). Our previous studies have shown that, at the RNA level, a high Δ40p53:p53 ratio is signi cantly associated with worse disease-free survival in breast cancer (6,11), and that at the protein level, Δ40p53 is expressed in a small subpopulation of cells within the microenvironment of invasive ductal carcinomas (IDCs) (25) and breast cancer cell lines (20). Thus, endogenously expressed Δ40p53 may adversely affect survival by promoting treatment resistance and recurrence, traits typically associated with cancer stem cells (CSCs).…”

Section: Introductionmentioning

confidence: 99%

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p53 isoform expression promotes a stemness phenotype and inhibits doxorubicin sensitivity in breast cancer

Reinhardt

Groen

Zhang

et al. 2023

Preprint

Self Cite

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In breast cancer, dysregulated TP53 expression signatures are a better predictor of chemotherapy response and survival outcomes than TP53 mutations. Our previous studies have shown that high levels of Δ40p53 are associated with worse disease-free survival and disruption of p53-induced DNA damage response in breast cancers. Here, we further investigated the in vitro and in vivo implications of Δ40p53 expression in breast cancer. We have shown that genes associated with cell differentiation are downregulated whilst those associated with stem cell regulation are upregulated in invasive ductal carcinomas expressing high levels of Δ40p53. In contrast to p53, endogenous ∆40p53 co-localised with the stem cell markers Sox2, Oct4, and Nanog in MCF-7 and ZR75-1 cell lines. ∆40p53 and Sox2 co-localisation was also detected in breast cancer specimens. Further, in cells expressing a high ∆40p53:p53 ratio, increased expression of stem cell markers, greater mammosphere and colony formation capacities, and downregulation of miR-145 and miR-200 (p53-target microRNAs that repress stemness) were observed compared to the control subline. In vivo, a high ∆40p53:p53 ratio led to increased tumour growth, Ki67 and Sox2 expression, and blood microvessel areas in the vehicle-treated mice. High expression of ∆40p53 also reduced tumour sensitivity to doxorubicin compared to control tumours. Enhanced therapeutic efficacy of doxorubicin was observed when transiently targeting Δ40p53 or when treating cells with OTSSP167 with concomitant chemotherapy. Taken together, high Δ40p53 levels induce tumour growth and may promote chemoresistance by inducing a stemness phenotype in breast cancer; thus, targeting Δ40p53 in tumours which have a high Δ40p53:p53 ratio could enhance the efficacy of standard-of-care therapies such as doxorubicin.

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Targeting the p53 signaling pathway in cancers: Molecular mechanisms and clinical studies

Shen¹,

Wang²,

Mao³

et al. 2023

MedComm

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Tumor suppressor p53 can transcriptionally activate downstream genes in response to stress, and then regulate the cell cycle, DNA repair, metabolism, angiogenesis, apoptosis, and other biological responses. p53 has seven functional domains and 12 splice isoforms, and different domains and subtypes play different roles. The activation and inactivation of p53 are finely regulated and are associated with phosphorylation/acetylation modification and ubiquitination modification, respectively. Abnormal activation of p53 is closely related to the occurrence and development of cancer. While targeted therapy of the p53 signaling pathway is still in its early stages and only a few drugs or treatments have entered clinical trials, the development of new drugs and ongoing clinical trials are expected to lead to the widespread use of p53 signaling‐targeted therapy in cancer treatment in the future. TRIAP1 is a novel p53 downstream inhibitor of apoptosis. TRIAP1 is the homolog of yeast mitochondrial intermembrane protein MDM35, which can play a tumor‐promoting role by blocking the mitochondria‐dependent apoptosis pathway. This work provides a systematic overview of recent basic research and clinical progress in the p53 signaling pathway and proposes that TRIAP1 is an important therapeutic target downstream of p53 signaling.

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Alterations in the p53 isoform ratio govern breast cancer cell fate in response to DNA damage

Cited by 11 publications

References 78 publications

Increased Expression of the Δ133p53β Isoform Enhances Brain Metastasis

Increased Expression of the Δ133p53β Isoform Enhances Brain Metastasis

p53 isoform expression promotes a stemness phenotype and inhibits doxorubicin sensitivity in breast cancer

Targeting the p53 signaling pathway in cancers: Molecular mechanisms and clinical studies

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