<i>TP53</i> mutation‐correlated genes predict the risk of tumor relapse and identify MPS1 as a potential therapeutic kinase in <i>TP53</i>‐mutated breast cancers

Győrffy, Balázs; Bottai, Giulia; Lehmann-Che, Jacqueline; Kéri, Gÿorgý; Őrfi, László; Inomata, Takayuki; Desmedt, Christine; Bianchini, Giampaolo; Turner, Nicholas C.; André, Fabrice; Sotiriou, Christos; Hortobágyi, Gabriel N.; Leo, Angelo Di; Pusztai, Lajos; Santarpia, Libero

doi:10.1016/j.molonc.2013.12.018

Cited by 64 publications

(53 citation statements)

References 56 publications

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“…While examining relationships between Snail1 mRNA expression levels and clinical outcomes 13,14 , we noted an inverse relationship between Snail1 levels and relapse-free survival (RFS) in patients expressing wild-type, but not mutant, TP53 (Fig. 1a).…”

Section: Resultsmentioning

confidence: 94%

Snail1-dependent p53 repression regulates expansion and activity of tumour-initiating cells in breast cancer

et al. 2016

Nat Cell Biol

103

121

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The zinc-finger transcription factor Snail1 is inappropriately expressed in breast cancer and associated with poor prognosis. While interrogating human databases, we uncovered marked decreases in relapse-free survival of breast cancer patients expressing high Snail1 levels in tandem with wild-type, but not mutant, p53. Using a Snail1 conditional knockout model of mouse breast cancer that maintains wild-type p53, we find that Snail1 plays an essential role in tumour progression by controlling the expansion and activity of tumour-initiating cells in preneoplastic glands and established tumours, whereas it is not required for normal mammary development. Growth and survival of preneoplastic as well as neoplastic mammary epithelial cells is dependent on the formation of a Snail1/HDAC1/p53 tri-molecular complex that deacetylates active p53, thereby promoting its proteasomal degradation. Our findings identify Snail1 as a molecular bypass that suppresses the anti-proliferative and pro-apoptotic effects exerted by wild-type p53 in breast cancer.

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Section: Resultsmentioning

confidence: 94%

Snail1-dependent p53 repression regulates expansion and activity of tumour-initiating cells in breast cancer

et al. 2016

Nat Cell Biol

103

121

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“…TP53 −/− cells treated with SP600125 failed to undergo cell cycle arrest and became polyploid upon mitotic abortion, resulting in apoptosis. The gene that encodes MPS1 is also significantly correlated with p53 mutation in several breast cancer datasets (107). Similarly, the inhibition of MSP1 by SP600125 reduced cell viability and increased cell death selectively in p53-mutant breast cancers (107).…”

Section: Targeting Pathways That Are Critical For Survival Of P53 Mutmentioning

confidence: 99%

“…The gene that encodes MPS1 is also significantly correlated with p53 mutation in several breast cancer datasets (107). Similarly, the inhibition of MSP1 by SP600125 reduced cell viability and increased cell death selectively in p53-mutant breast cancers (107). In addition, MSP1 inhibition sensitized breast cancers to conventional chemotherapy treatments (107).…”

Section: Targeting Pathways That Are Critical For Survival Of P53 Mutmentioning

confidence: 99%

Molecularly targeted therapies for p53-mutant cancers

Zhao

Tahaney

Mazumdar

et al. 2017

Cell. Mol. Life Sci.

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The tumor suppressor p53 is lost or mutated in approximately half of human cancers. Mutant p53 not only loses its anti-tumor transcriptional activity, but often acquires oncogenic functions to promote tumor proliferation, invasion, and drug resistance. Traditional strategies have been taken to directly target p53 mutants through identifying small molecular compounds to deplete mutant p53, or to restore its tumor suppressive function. Accumulating evidence suggest that cancer cells with mutated p53 often exhibit specific functional dependencies on secondary genes or pathways to survive, providing alternative targets to indirectly treat p53-mutant cancers. Targeting these genes or pathways, critical for survival in the presence of p53 mutations, holds great promise for cancer treatment. In addition, mutant p53 often exhibits novel gain-of-functions to promote tumor growth and metastasis. Here, we review and discuss strategies targeting mutant p53, with focus on targeting the mutant p53 protein directly, and on the progress of identifying genes and pathways required in p53-mutant cells.

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“…We have also investigated if the expression of CDK8 and its interactive genes correlates with the p53 mutation status, using Affymetrix microarray gene expression data in 319 patients with known p53 status, as described [33]. The results, presented in Fig.…”

Section: Elevated Expression Of Cdk8 Cdk19 Ccnc and Myc Is Associatmentioning

confidence: 99%

Expression of CDK8 and CDK8-interacting Genes as Potential Biomarkers in Breast Cancer

Broude

Győrffy²,

Chumanevich³

et al. 2015

CCDT

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CDK8 and its paralog CDK19, in complex with CCNC, MED12 and MED13, are transcriptional regulators that mediate several carcinogenic pathways and the chemotherapy-induced tumor-supporting paracrine network. Following up on our previous observation that CDK8, CDK19 and CCNC RNA expression is associated with shorter relapse-free survival (RFS) in breast cancer, we now found by immunohistochemical analysis that CDK8/19 protein is overexpressed in invasive ductal carcinomas relative to non-malignant mammary tissues. Meta-analysis of transcriptomic data revealed that higher CDK8 expression is associated with shorter RFS in all molecular subtypes of breast cancer. These correlations were much stronger in patients who underwent systemic adjuvant therapy, suggesting that CDK8 impacts the failure of systemic therapy. The same associations were found for CDK19, CCNC and MED13. In contrast, MED12 showed the opposite association with a longer RFS. The expression levels of CDK8 in breast cancer samples were directly correlated with the expression of MYC, as well as CDK19, CCNC and MED13 but inversely correlated with MED12. CDK8, CDK19 and CCNC expression was strongly increased and MED12 expression was decreased in tumors with mutant p53. Gene amplification is the most frequent type of genetic alterations of CDK8, CDK19, CCNC and MED13 in breast cancers (9.7% of which have amplified MED13), whereas point mutations are more common in MED12. These results suggest that the expression of CDK8 and its interactive genes has a profound impact on the response to adjuvant therapy in breast cancer in accordance with the role of CDK8 in chemotherapy-induced tumor-supporting paracrine activities.

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TP53 mutation‐correlated genes predict the risk of tumor relapse and identify MPS1 as a potential therapeutic kinase in TP53‐mutated breast cancers

Abstract: Keywords:Breast cancer subtypes

Cited by 64 publications

References 56 publications

Snail1-dependent p53 repression regulates expansion and activity of tumour-initiating cells in breast cancer

Snail1-dependent p53 repression regulates expansion and activity of tumour-initiating cells in breast cancer

Molecularly targeted therapies for p53-mutant cancers

Expression of CDK8 and CDK8-interacting Genes as Potential Biomarkers in Breast Cancer

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