Somatic Trp53 mutations differentially drive breast cancer and evolution of metastases

Zhang, Yun; Xiong, Shunbin; Liu, Bin; Pant, Vinod; Celii, F. G.; Chau, Gilda; Elizondo-Fraire, Ana C.; Yang, Peirong; You, M. James; El‐Naggar, Adel K.; Navin, Nicholas E.; Lozano, Guillermina

doi:10.1038/s41467-018-06146-9

Cited by 49 publications

(58 citation statements)

References 38 publications

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“…In vivo models highlight the aggressive nature of TP53 somatic mutations and the parallel tumor evolution pattern driven by a TP53 missense mutation as the initiating event. In addition, TP53 mutations are the most frequent genetic alterations in breast cancer and are associated with more aggressive disease and worse overall survival [31]. These results were in keeping with previously published data which have shown that mutant p53 enhances tumor development which involves the expansion of CSCs sub-populations within these tumors and that mutant p53 facilitates the acquisition of CSCs phenotype [32].…”

Section: Discussionsupporting

confidence: 89%

TP53 Mutation in Saudi Breast Cancer Patients: Correlations with Cancer Stem Cell Markers Expression and Clinicopathological Variables

Nassir¹,

Elmoneim²,

Esheba³

et al. 2020

SJPM

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Background: Breast cancer is one of the most common cancers with a high mortality rate worldwide including Saudi Arabia. It is characterized by the presence of both intra-and inter-tumor heterogeneity. It describes the origin of this heterogeneity to the cancer stem cells (CSC). Breast cancer stem cells are characterized by the expression of the surface markers CD44 and lack or very low expression of CD24. Objectives: To assess cancer stem cell markers (CD44 andCD24) in 126 breast cancer cases by immunohistochemistry and study their association with a different type of TP53 gene mutations by applying next-generation sequencing (NGS). In addition to analyze the association between these markers and the clinicopathological characteristics. Results: CD44 expression was significantly associated with lymph node metastasis, tumor grade, stage (each P<0.0001), and ER expression (P = 0.016). CD24 expression was found to be associated with lymph node metastasis and ER only. For the molecular analysis, the number of mutations per case was significantly associated with the advanced stage of breast cancer (p = 0.004). Also, missense mutation was highly associated with CD44 and CD24 (p=0.04, p=0.005), respectively. Stop-gained mutation and Frameshift mutation both were associated with CD44 only (p=0.01, p=0.05), respectively. Finally, the synonymous mutation was only associated with the stage of cancer (p=0.01). Conclusion, we believe that the combination of CD44, CD24, TP53 and TP53 gene mutations can be prognostic factors for breast cancer patients and the information obtained may contribute to the development of a treatment.

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Section: Discussionsupporting

confidence: 89%

TP53 Mutation in Saudi Breast Cancer Patients: Correlations with Cancer Stem Cell Markers Expression and Clinicopathological Variables

Nassir¹,

Elmoneim²,

Esheba³

et al. 2020

SJPM

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“…These GO terms were found mainly to be associated with DNA replication origin binding and chromosome centromeric region. The KEGG pathways analysis showed that the co-expressed genes were involved in p53 signaling pathway, oocyte meiosis, and homologous recombination (Figures 6A,B), which were closely associated with the tumorigenesis and development of BC as described in previous studies (23)(24)(25)(26).…”

Section: Functional Enrichment Analysis Of the 10-lncrna Signaturesupporting

confidence: 64%

Individualized Prediction of Survival by a 10-Long Non-coding RNA-Based Prognostic Model for Patients With Breast Cancer

Yang

Wang

et al. 2020

Front. Oncol.

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Deregulations of long non-coding RNAs (lncRNAs) have been implicated in the progression of breast cancer (BC). However, the prognostic values of those lncRNAs in BC remain elusive. This study aimed at constructing a lncRNA-based prognostic model to improve the clinical management of BC. Systematic investigation of lncRNA expression profiles and clinical data from The Cancer Genome Atlas (TCGA) database were utilized to establish a 10-lncRNA signature. The prognostic signature efficiently discriminated patients with significantly different prognosis regardless of intrinsic molecular subtypes and tumor-node-metastasis (TNM) stage. A combined model was constructed by multivariate Cox proportional hazards regression (CPHR) analysis, which combined the lncRNA-based signature with certain clinical risk factors (TNM stage, age, and human epidermal growth factor receptor 2 status). This model predicted a survival probability that closely corresponds to the actual survival probability. With respect to the entire set, the time-dependent receiver-operating characteristic curves revealed that the area under the curve of this model was the highest than any of the clinical risk factors. Moreover, functional enrichment analysis indicated that the molecular signature was mainly involved in DNA replication, which was firmly related to BC tumorigenesis. Consistent with the discovery, the knockdown of LHX1-DT, one of the 10 prognostic lncRNAs, attenuated the proliferation of BC cells in vitro and in vivo. Taken together, our study constructed a novel 10-lncRNA signature for prediction prognosis, and the signature-based model could provide new insight into accurate management of BC patients.

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“…The latter study not only demonstrated the oncogenic GOF of mouse p53 mutants R172H and R270H, but also ascertained the differential effects of the DNA-contact (R270H) and conformational (R172H) mutants on tumorigenesis (Olive et al, 2004). Additionally, a recent study has revealed that mutant p53-R172H and R245W (equivalent to human R248W) differentially prompt breast cancer development by generating somatic mutations in murine mammary epithelial cells (Zhang et al, 2018). Altogether, these genetic studies elegantly depict the role of the cancer-associated hotspot mutants in vivo (Donehower and Lozano, 2009).…”

Section: Gain-of-functions Of Mutant P53mentioning

confidence: 99%

Mutant p53 in cancer therapy—the barrier or the path

Zhou

Hao

2018

Journal of Molecular Cell Biology

197

135

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Since wild-type p53 is central for maintaining genomic stability and preventing oncogenesis, its coding gene TP53 is highly mutated in ~50% of human cancers, and its activity is almost abrogated in the rest of cancers. Approximately 80% of p53 mutations are single point mutations with several hotspot mutations. Besides loss of function and dominant-negative effect on the wild-type p53 activity, the hotspot p53 mutants also acquire new oncogenic functions, so-called ‘gain-of-functions’ (GOF). Because the GOF of mutant p53 is highly associated with late-stage malignance and drug resistance, these p53 mutants have become hot targets for developing novel cancer therapies. In this essay, we review some recent progresses in better understanding of the role of mutant p53 GOF in chemoresistance and the underlying mechanisms, and discuss the pros and cons of targeting mutant p53 for the development of anti-cancer therapies.

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Somatic Trp53 mutations differentially drive breast cancer and evolution of metastases

Cited by 49 publications

References 38 publications

TP53 Mutation in Saudi Breast Cancer Patients: Correlations with Cancer Stem Cell Markers Expression and Clinicopathological Variables

TP53 Mutation in Saudi Breast Cancer Patients: Correlations with Cancer Stem Cell Markers Expression and Clinicopathological Variables

Individualized Prediction of Survival by a 10-Long Non-coding RNA-Based Prognostic Model for Patients With Breast Cancer

Mutant p53 in cancer therapy—the barrier or the path

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