@article{2844d3d6d625422884cbb4e3361aedd8,
title = "Molecular portraits of cell cycle checkpoint kinases in cancer evolution, progression, and treatment responsiveness",
abstract = "Cell cycle dysregulation is prerequisite for cancer formation. However, it is unknown whether the mode of dysregulation affects disease characteristics. Here,we conduct comprehensive analyses of cell cycle checkpoint dysregulation using patient data and experimental investigations. We find that ATM mutation predisposes the diagnosis of primary estrogen receptor (ER)+/human epidermal growth factor (HER)2- cancer in older women. Conversely, CHK2 dysregulation induces formation of metastatic, premenopausal ER+/HER2- breast cancer (P = 0.001) that is treatment-resistant (HR = 6.15, P = 0.01). Lastly, while mutations in ATR alone are rare, ATR/TP53 co-mutation is 12-fold enriched over expected in ER+/HER2- disease (P = 0.002) and associates with metastatic progression (HR = 2.01, P = 0.006). Concordantly, ATR dysregulation induces metastatic phenotypes in TP53 mutant, not wild-type, cells. Overall, we identify mode of cell cycle dysregulation as a distinct event that determines subtype, metastatic potential, and treatment responsiveness, providing rationale for reconsidering diagnostic classification through the lens of the mode of cell cycle dysregulation.",
keywords = "Humans, Female, Aged, Breast Neoplasms/drug therapy, Epidermal Growth Factor, Cell Cycle/genetics, Cell Division, Mutation, Receptors, Estrogen",
author = "Elena Oropeza and Sinem Seker and Sabrina Carrel and Aloran Mazumder and Daniel Lozano and Athena Jimenez and VandenHeuvel, {Sabrina N.} and Noltensmeyer, {Dillon A.} and Punturi, {Nindo B.} and Lei, {Jonathan T.} and Bora Lim and Waltz, {Susan E.} and Raghavan, {Shreya A.} and Bainbridge, {Matthew N.} and Svasti Haricharan",
note = "Funding Information: Acknowledgments Funding:ThisworkwassupportedbytheKomenCCR18548157,A CS 978170,andNCIK22 CA229613(toS.H.);theCaliforniaInstituteforRegenerativeMedicine,EDUC4-12813(toA.M.), NCIR21CA263768,andNCIR37CA269224;theT exasA&MTriadsforTransformationFunds(to S.A.R.); and the Tr ansla tional Breast Cancer Research Training Program grant T32CA203690 (to J.T .L.). In addition, B.L. received research funding from Takeda Oncology, Merck, Genentech, PumaBiotechnology,Celcuity,EliLilly,Calithera,NIH,DOD,ChanandZuckerbergInstitute,and AdoptaScientistprogram.ThisworkwasalsosupportedbytheT exasA&MEngineering ExperimentStation.Authorcontributions:Datacollection,curation,andanalysis:E.O.,S.S., A.J.,N.B.P ., D.L.,A.M.,S.N.V ., D.A.N.,J.T .L., B.L.,S.E.W ., S.A.R.,M.N.B.,andS.H.Conceptual oversight:M.N.B.andS.H.Preparingmanuscript:E.O.,S.S.,S.C.,N.P ., andS.H.Writingandediting ofmanuscript:E.O.,S.S.,S.C.,A.M.,B.L.,S.E.W ., S.A.R.,M.N.B.,andS.H.Competinginterests:The authors declared the following potential conflicts of interest in respect to the research, authorship, and/or publication of this article: B.L. holds consultancy roles for Celcuity, Natera, Daichi-Sankyo,Novartis,Pfizer,andAstraZeneca,aswellashonorariafromPuma Biotechnology,Novartis,andPfizer.Theauthorsdeclarethattheyhav enoothercompeting interests.Dataandmaterialsavailability:Thedatasetswerederivedfromsourcesinthe publicdomain:TCGA:CancerGenomeAtlasNetworkatwww.cancer.gov/about-nci/ organization/ccg/research/structural-genomics/tcgaandcBioPortal(www.cbioportal.org/ study/summary?id=brca_tcga_pub);MET ABRIC: cBioPortal(www.cbioportal.org/study/ summary?id=brca_metabric);MSKCC:DOI(doi.org/10.1016/j.ccell.2018.08.008,CancerCell 2018);BRO AD: cBioPortal(www.cbioportal.org/study/summary?id=brca_broad);andMBCP: TheMetastaticBreastCancerProject(www.mbcproject.org)andcBioPortal(www.cbioportal. org/study/summary?id=brca_mbcproject_wagle_2017).Alldataneededtoevaluatethe conclusionsinthepaperarepresentinthepaperand/ortheSupplementaryMaterials.Citation diversitystatement:Itisestablishedacrossacademicfieldsthatpapersauthoredbyscientists whoarewhiteandAsianmenareov er citedcomparedtothoseauthoredbyscientistsfrom historicallyexcludedgroups(includingwomen).Inanefforttoaddressthesecitationbiases,we have compiled gender and race of each first and last author cited in this paper. W e were then abletodeterminetheproportionofpapersauthoredbyscientistsfromhistoricallyexcluded groupscomparedtothoseauthoredbyscientistswhoidentifyaswhiteorAsianmen.Inthis article,56.1%ofthepaperscitedwereauthoredbyatleastonewomaninaseniorposition (eitherfirstorlast),15.8%wereauthoredbyatleastonenon-whiteauthorinaseniorposition, and10.5%wereundetermined. Publisher Copyright: {\textcopyright} 2023 The Authors.",
year = "2023",
month = jun,
day = "30",
doi = "10.1126/sciadv.adf2860",
language = "English (US)",
volume = "9",
pages = "eadf2860",
journal = "Science advances",
issn = "2375-2548",
publisher = "American Association for the Advancement of Science",
number = "26",
}