title: Hot Spot Mutation in TP53 (R248Q) Causes Oncogenic Gain-of-Function Phenotypes in a Breast Cancer Cell Line Derived from an African American patient.
abstract: African American (AA) breast cancer patients often have triple negative breast cancer (TNBC) that contains mutations in the TP53 gene. The point mutations at amino acid residues R273 and R248 both result in oncogenic gain-of-function (GOF) phenotypes. Expression of mutant p53 (mtp53) R273H associates with increased cell elasticity, survival under serum deprivation conditions, and increased Poly (ADP ribose) polymerase 1 (PARP1) on the chromatin in the AA-derived TNBC breast cancer cell line MDA-MB-468. We hypothesized that GOF mtp53 R248Q expression could stimulate a similar phenotype in the AA-derived TNBC cell line HCC70. To test this hypothesis we depleted the R248Q protein in the HCC70 cell line using shRNA-mediated knockdown. Using impedance-based real-time analysis we correlated the expression of mtp53 R248Q with increased cell deformability. We also documented that depletion of mtp53 R248Q increased PARP1 in the cytoplasm and decreased PARP1 on the chromatin. We conclude that in the AA-derived TNBC HCC70 cells mtp53 R248Q expression results in a causative tumor associated phenotype. This study supports using the biological markers of high expression of mtp53 R273H or R248Q as additional diagnostics for TNBC resistant subtypes often found in the AA community. Each mtp53 protein must be considered separately and this work adds R248Q to the increasing list of p53 mutations that can be used for diagnostics and drug targeting. Here we report that when R248Q mtp53 proteins are expressed in TNBC, then targeting the gain-of-function pathways may improve treatment efficacy.
authors.affiliation: Department of Biological Sciences, Hunter College, City University of New York, New York, NY 10065, USA. nataly.shtraizent@mssm.edu.|Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. nataly.shtraizent@mssm.edu.
authors.forename: Nataly
authors.initials: N
authors.lastname: Shtraizent
authors.affiliation: Department of Chemistry, Hunter College, City University of New York, New York, NY 10065, USA. hmatsui@hunter.cuny.edu.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matsui
authors.affiliation: Department of Biological Sciences, Hunter College, City University of New York, New York, NY 10065, USA. polotskaia@genectr.hunter.cuny.edu.
authors.forename: Alla
authors.initials: A
authors.lastname: Polotskaia
authors.affiliation: Department of Biological Sciences, Hunter College, City University of New York, New York, NY 10065, USA. bargonetti@genectr.hunter.cuny.edu.
authors.forename: Jill
authors.initials: J
authors.lastname: Bargonetti
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D064726:Triple Negative Breast Neoplasms / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D016159:Tumor Suppressor Protein p53
keywords: African American; TNBC; deformability; impedance; p53