Multidimensional quantitative phenotypic and molecular analysis reveals neomorphic behaviors of p53 missense mutants

Pal, Anasuya; Gonzalez-Malerva, Laura; Eaton, Seron; Xu, Chenxi; Zhang, Yining; Grief, Dustin; Sakala, Lydia; Nwekwo, Lilian; Zeng, Jia; Christensen, Grant; Gupta, Chitrak; Streitwieser, Ellen; Singharoy, Abhishek; Park, Jin G.; LaBaer, Joshua

doi:10.1038/s41523-023-00582-7

Title: Multidimensional quantitative phenotypic and molecular analysis reveals neomorphic behaviors of p53 missense mutants

Journal Article · Fri Sep 29 00:00:00 EDT 2023 · npj Breast Cancer

DOI:https://doi.org/10.1038/s41523-023-00582-7· OSTI ID:2007129

Pal, Anasuya; Gonzalez-Malerva, Laura; Eaton, Seron; Xu, Chenxi; Zhang, Yining; Grief, Dustin; Sakala, Lydia;

; Zeng, Jia; Christensen, Grant; Gupta, Chitrak;

; Singharoy, Abhishek;

;

Abstract Mutations in the TP53 tumor suppressor gene occur in >80% of the triple-negative or basal-like breast cancer. To test whether neomorphic functions of specific TP53 missense mutations contribute to phenotypic heterogeneity, we characterized phenotypes of non-transformed MCF10A-derived cell lines expressing the ten most common missense mutant p53 proteins and observed a wide spectrum of phenotypic changes in cell survival, resistance to apoptosis and anoikis, cell migration, invasion and 3D mammosphere architecture. The p53 mutants R248W, R273C, R248Q, and Y220C are the most aggressive while G245S and Y234C are the least, which correlates with survival rates of basal-like breast cancer patients. Interestingly, a crucial amino acid difference at one position—R273C vs. R273H—has drastic changes on cellular phenotype. RNA-Seq and ChIP-Seq analyses show distinct DNA binding properties of different p53 mutants, yielding heterogeneous transcriptomics profiles, and MD simulation provided structural basis of differential DNA binding of different p53 mutants. Integrative statistical and machine-learning-based pathway analysis on gene expression profiles with phenotype vectors across the mutant cell lines identifies quantitative association of multiple pathways including the Hippo/YAP/TAZ pathway with phenotypic aggressiveness. Further, comparative analyses of large transcriptomics datasets on breast cancer cell lines and tumors suggest that dysregulation of the Hippo/YAP/TAZ pathway plays a key role in driving the cellular phenotypes towards basal-like in the presence of more aggressive p53 mutants. Overall, our study describes distinct gain-of-function impacts on protein functions, transcriptional profiles, and cellular behaviors of different p53 missense mutants, which contribute to clinical phenotypic heterogeneity of triple-negative breast tumors.

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Sponsoring Organization:: USDOE

Grant/Contract Number:: AC05-00OR22725

OSTI ID:: 2007129

Journal Information:: npj Breast Cancer, Journal Name: npj Breast Cancer Vol. 9 Journal Issue: 1; ISSN 2374-4677

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: Country unknown/Code not available

Language:: English

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Mutant p53 exerts a dominant negative effect by preventing wild-type p53 from binding to the promoter of its target genes Willis, Amy; Jung, Eun Joo; Wakefield, Therese Oncogene, Vol. 23, Issue 13 https://doi.org/10.1038/sj.onc.1207396	journal	January 2004
Mutant p53 oncogenic functions in cancer stem cells are regulated by WIP through YAP/TAZ Escoll, M.; Gargini, R.; Cuadrado, A. Oncogene, Vol. 36, Issue 25 https://doi.org/10.1038/onc.2016.518	journal	February 2017
Two hot spot mutant p53 mouse models display differential gain of function in tumorigenesis Hanel, W.; Marchenko, N.; Xu, S. Cell Death & Differentiation, Vol. 20, Issue 7 https://doi.org/10.1038/cdd.2013.17	journal	March 2013

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