Mutant p53 in breast cancer: potential as a therapeutic target and biomarker

Duffy, Michael J.; Synnott, Naoise C; Crown, John

doi:10.1007/s10549-018-4753-7

Cited by 163 publications

(129 citation statements)

References 62 publications

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“…Several drugs were identified as p53 interacting compounds, either on the wild-type or the mutated p53 proteins ( Figure 5 C). This is the case of ellipticine binding to wild-type p53 (WT-p53) resulting in an increase in its nuclear localization and subsequent p21 promoter transactivation, as well as to the oncogenic mutated p53 (mut-p53) present in multiple cancers and hemopathies [ 187 , 188 , 189 ] to restore its normal conformation and activity [ 190 ]. Mut-p53 reactivation to restore normal p53 function is also obtained upon treatment with CP-31398, Reactivation of p53 and Induction of Tumor Cell Apoptosis (RITA), STIMA-1 or PRIMA-1 as reversible or covalent binders of mut-p53 ( Figure 5 ) [ 191 , 192 ].…”

Section: Targeting Transcription Factor Through a Binding Pocketmentioning

confidence: 99%

Targeting Transcription Factors for Cancer Treatment

et al. 2018

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Transcription factors are involved in a large number of human diseases such as cancers for which they account for about 20% of all oncogenes identified so far. For long time, with the exception of ligand-inducible nuclear receptors, transcription factors were considered as “undruggable” targets. Advances knowledge of these transcription factors, in terms of structure, function (expression, degradation, interaction with co-factors and other proteins) and the dynamics of their mode of binding to DNA has changed this postulate and paved the way for new therapies targeted against transcription factors. Here, we discuss various ways to target transcription factors in cancer models: by modulating their expression or degradation, by blocking protein/protein interactions, by targeting the transcription factor itself to prevent its DNA binding either through a binding pocket or at the DNA-interacting site, some of these inhibitors being currently used or evaluated for cancer treatment. Such different targeting of transcription factors by small molecules is facilitated by modern chemistry developing a wide variety of original molecules designed to specifically abort transcription factor and by an increased knowledge of their pathological implication through the use of new technologies in order to make it possible to improve therapeutic control of transcription factor oncogenic functions.

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Section: Targeting Transcription Factor Through a Binding Pocketmentioning

confidence: 99%

Targeting Transcription Factors for Cancer Treatment

et al. 2018

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“…Being a transcriptional factor, p53 plays a key role in the maintenance of genome integrity by regulating such important processes as cell cycle progression, apoptosis, senescence, DNA repair, and cell metabolism in response to various forms of cell stress. Perhaps not surprisingly, the TP53 gene is the most commonly mutated gene in various tumors including breast cancer [50][51][52][53] . Importantly, about 30% of all breast cancer cases are characterized by mutations in the TP53 gene, while for HER2-positive subtypes, the proportion of TP53 mutations reaches 70% 54,55 .…”

Section: The P53 Family Of Tumor Suppressors In Breast Cancermentioning

confidence: 99%

Attenuation of p53 mutant as an approach for treatment Her2-positive cancer

et al. 2020

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Breast cancer is one of the world’s leading causes of oncological disease-related death. It is characterized by a high degree of heterogeneity on the clinical, morphological, and molecular levels. Based on molecular profiling breast carcinomas are divided into several subtypes depending on the expression of a number of cell surface receptors, e.g., ER, PR, and HER2. The Her2-positive subtype occurs in ~10–15% of all cases of breast cancer, and is characterized by a worse prognosis of patient survival. This is due to a high and early relapse rate, as well as an increased level of metastases. Several FDA-approved drugs for the treatment of Her2-positive tumors have been developed, although eventually cancer cells develop drug resistance. These drugs target either the homo- or heterodimerization of Her2 receptors or the receptors’ RTK activity, both of them being critical for the proliferation of cancer cells. Notably, Her2-positive cancers also frequently harbor mutations in the TP53 tumor suppressor gene, which exacerbates the unfavorable prognosis. In this review, we describe the molecular mechanisms of RTK-specific drugs and discuss new perspectives of combinatorial treatment of Her2-positive cancers through inhibition of the mutant form of p53.

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“…Tumor protein p53 (TP53) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA) were revealed as mutant genes in breast cancer 20,21 . As shown in Fig.…”

Section: Cldn11 High Expression Is Associated With Better Os and Dfs mentioning

confidence: 99%

The Expression of CLDN11 in Invasive Ductal and Invasive Lobular Breast Cancer and Multivariate Prognostic Analysis

Du¹,

Zhang²,

Feng³

et al. 2020

Preprint

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Background: Breast cancer (BRCA) remains the most common malignancy among women worldwide. Invasive ductal (IDC) and invasive lobular breast cancer (ILC) are the most frequent histological subtypes. Many genetic heterogeneities are related to the carcinogenesis of breast cancer, but exact reasons are still unclear. The study aimed to perform a clinical multivariate analysis of CLDN11 in ILC and IDC. Methods: Datasets analyzed CLDN11 expression in IDC and ILC from The Cancer Genome Atlas (TCGA) database, and the multiple analysis of stratification in terms of clinical pathologic features and CLDN11 was using the Chi-square test. Results: CLDN11 expression was significantly decreased in IDC and ILC data of GEO and TCGA compared to the normal breast tissues. Besides, CLDN11 is negatively correlated with pro-oncogene IKBKE expression and positively correlated with tumor suppressor ETS1 expression in IDC and ILC samples. Multiple factors, including age, clinical stage, subtype, and mutation status, indicated that the expression of CLDN11 is positively associated with the progression of IDC and ILC.Conclusions: CLDN11 acted as a tumor suppressor in IDC and ILC patients and serves as a drug-gable target against IDC and ILC.

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Mutant p53 in breast cancer: potential as a therapeutic target and biomarker

Abstract: Since p53 is mutated in the vast majority of TN breast cancers, compounds such as APR-246, PK11007, and COTI-2 are potential treatments for patients with this subform of the disease. Further research is necessary to identify a potential biomarker role for mutant p53 in breast cancer.

Cited by 163 publications

References 62 publications

Targeting Transcription Factors for Cancer Treatment

Targeting Transcription Factors for Cancer Treatment

Attenuation of p53 mutant as an approach for treatment Her2-positive cancer

The Expression of CLDN11 in Invasive Ductal and Invasive Lobular Breast Cancer and Multivariate Prognostic Analysis

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