Abstract

TheMre11-Rad50-Nbs1complexisapleiotropicsensorofDNAdoublestrandbreaksthatpromotesATM signaling,cellcyclecheckpointactivation,andDNArepair.WehaverecentlyshownthatMre11isanessential componentofthetumorsuppressiveDNAdamageresponse(DDR)inamurinemodelofbreastcancer.Mre11 pathwaydeficiencyhasalsobeenreportedinasignificantfractionofhumantriplenegative (estrogen/progesteronereceptornegative,HER2non-amplified)breastcancers(TNBC),whichare characterizedbyrampantchromosomalinstabilityandnearlyuniversalinactivationofthep53pathway.Inthis project,wewillinvestigatearoleforMre11-mediatedtumorsuppressioninmurinemodelsofTNBCinitiatedby c-Mycoverexpression,Rb1deletion,and/orp53deficiency.
In Aim1, wewillanalyzetheeffectofMre11 deficiencyoncellcyclecheckpointactivationinresponsetooncogene-inducedDNAdamage.Timelapse microscopyofDNAdamageandcellcyclestatetransitionswillbeperformedinpreneoplasticprimary mammaryepithelialcells.
In Aim2, wewillusesinglecellwholegenomesequencingtoquantifystochastic chromosomalaberrationsthataccumulateduringoncogene-inducedreplicationstressinprimarymammary epithelialcells.TheeffectofMre11and/orp53deficiencyonthechromosomalinstabilityphenotypeatdifferent stagesoftumorigenesiswillbeanalyzed.
In Aim3, wewillengineerMre11mutationsinaRb1/p53-deficient murineTNBCmodeltomeasureeffectsontumorlatency.Geneexpressionandgenomicscarsignatures associatedwithMre11deficientbreastcancerswillbedetermined,andcomparedtosignaturesofBrca1 deficiency.ApanelofpharmacologicalDDRpathwayinhibitorswillbetestedtoidentifytargetablesynthetic lethalvulnerabilitiesofMre11deficiency.Collectively,thisprojectwillprovideinsightintop53-independent mechanismsofMre11-mediatedtumorsuppression,andidentifymolecularsignaturesandtherapeutic susceptibilitiesofMre11deficientbreastcancer.

Public Health Relevance

ThisprojectwillinvestigatehowdeficiencyinacriticalsensorofDNAdoublestrandbreaks(Mre11)promotes thedevelopmentoftriplenegativebreastcancer(estrogen/progesteronereceptornegative,HER2non- amplified).WewillelucidatemolecularprofilesandtherapeuticvulnerabilitiesofMre11deficientbreastcancer. Thesestudiesmayengendernovelapproachestobothpreventandtreattriplenegativebreastcancer.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37CA227837-03
Application #
10064081
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Witkin, Keren L
Project Start
2018-12-01
Project End
2023-11-30
Budget Start
2020-12-01
Budget End
2021-11-30
Support Year
3
Fiscal Year
2021
Total Cost
Indirect Cost

  Institution

Name
University of North Carolina Chapel Hill
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599