Breastcanceristhemostprevalentcanceramongwomenandleadstoabout40,000metastaticrelateddeaths annuallyintheUnitedStates.Circulatingtumorcells(CTCs)shedfromtheprimarytumorintothecirculatory system.TheseCTCsarethendisplacedindistantorganswheremetastatictumorseventuallyarise.Distinctive breastcancerCTCsareassumedtoresultfromdiscretepatternsofmutatedcancergenes.Nonetheless,the contribution of epigenetic changes to the development of individual CTC characteristics is unknown. DNA methylationatcytosinesinCpGdinucleotidesiscriticalinprogramminggeneexpressionanditsdisruptionisa typical hallmark of cancer. Vertebrate CpG islands are short spreads of DNA sequences that differ from the typicalgenomicpatternbybeingGC-richandpredominantlyunmethylated.Incancercells,someCpGislands becomestronglymethylated,whichresultsinrepressionofgenetranscription.Additionally,partiallymethylated domains(PMDs)arefoundingenepoorregionswhichcorrespondtolamina-attachmentdomains.PMDsare thoughttobelinkedtogeneexpression,butnotenoughisknownaboutwhytheircorrespondingdomainsexist orabouttheirsinglecellcomposition.Methylomeshavealsobeenlinkedtoenhancersthatcontrolacohortof gene expression. Our lab has established several patient-derived CTC lines, allowing me to analyze the methylomes in CTCs for the first time. By studying the methylomes of CTCs using whole genome bisulfite sequencing (WGBS), I hope to understand if methylation patterns in CTCs are heterogeneous and how this variationcontributestometastasis.FindingsfromWGBSanalysishavedemonstratedthattheCTClinesBrx50 andBrx61appeartobelessmethylatedwhencomparedtotheCTClinesBrx07andBrx68.Intriguingly,Brx07 andBrx68aremoremetastaticwhencomparedtoBrx50andBrx61.Thesespecificareasthatvarybetweenthe CTCs?methylomescouldbepotentialareasofinterestformetastasis.

Public Health Relevance

PublicHealthRelevanceStatement CTCs hold the key to understanding the biology of metastasis and provides a biomarker to noninvasively measuretheevolutionoftumorgenotypesduringtreatmentanddiseaseprogressionofbreastcancer,therefore makingthemtargetsforthepreventionofmetastasis.IdentifyingDNAmethylationsignaturesinCTCswillextend our ability to classify breast cancer and to predict the prognosis by using methylation patterns, an outcome beyondwhatiscurrentlypossible.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31CA213970-02
Application #
9377487
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mcneil, Nicole E
Project Start
2016-12-01
Project End
2020-04-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Southern California
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90033