Abstract

Background:Postpartumbreastcancers,definedasbreastcancersdiagnosedwithin5-10yearsoflast childbirth,aremorethantwiceaslikelytobecomemetastaticandresultindeath.Thisdevastatingdiagnosis affectsthousandsofyoungwomenannually.Ourpreviousresearchrevealedthatnon-invasivebreasttumor cellsbecomeinvasiveandmetastaticinpostpartummicecomparedtocontrolsinnulliparousmice.Wealso revealedanovelfeedbackloopinvolvingcollagenmediatedupregulationofCOX-2,whichmediatesinvasion andmetastasisinpostpartummice.Subsequentgeneexpressionanalysisrevealedasignificantandspecific upregulationofSEMA7AmRNAinpostpartumbreasttumorcells.TheSEMA7Ageneencodesforsemaphorin 7a(Sema7a),asignalingmoleculethatdrivesneuraldevelopment,immunity,andtissueremodelinginthe lung.OurpreliminarydatademonstratethatsilencingofSEMA7Acelllinederivedpostpartumbreastcancer xenograftsdelaysgrowth,progressiontoinvasivecancer,andreduceslymphangiogenesisinthetumor microenvironment.Inaddition,wehaveanalyzedouryoungwomen?sbreastcancercohorttorevealthat SEMA7Aproteinissignificantlyincreasedinpostpartumpatienttumorsandinnulliparouspatienttumorsthat subsequentlyrecurred.Thus,wepostulatethatSEMA7Aisalsoageneralmediatorofbreasttumor progression.Insupportofthis,ourgeneexpressionanalysisofmultiplehumanbreastcancerdatasetsreveals thatSEMA7AmRNAexpressionisassociatedwithearlyrecurrence,metastasis,anddeath.Cumulatively, thesedatasupportthehypothesisthatSEMA7Apromotestumorprogressioninbreastcancerpatientsand maybeanimportanttherapeutictarget.Objective/Hypothesis:Acollagen-mediatedCOX-2/SEMA7A signalingaxisiskeyforinvasion,stromalremodeling,andinductionofvascularremodelinginthe tumormicroenvironment,allofwhichultimatelydrivemetastasis.
SpecificAims :(1)Determinehow collagenleadstoupregulationofCOX-2andSEMA7AandwhethertargetingCOX-2incombinationwith silencingofSEMA7Awillblocktumorcellinvasion.(2)DefinethemechanismsbywhichSEMA7Apromotes vascularremodelingandmetastasis,determinewhethertargetingorco-targetingofSEMA7AandCOX-2will blockmetastasis,anddefinetherelationshipbetweenSEMA7AandCOX-2inpostpartumbreasttumors. Cancerrelevance:Toestablishclinicalrelevance,wewillexaminetherelationshipbetweenSEMA7Aand COX-2proteinexpression,alongwithcollagenandthevasculature,usingmulti-colorimmunostainingand correlatewithinvasionandrecurrenceinourpostpartumbreastcancerpatienttissues.Theexpected outcomesareidentificationofmechanismsbywhichCOX-2andSEMA7Asupportbreasttumorprogression. Suchresultscouldpositivelyimpactthousandsofbreastcancerpatientsbydefiningnewtherapiestargetedat theSEMA7Apathway.GiventhatSEMA7Aexpressionisgenerallylowinadulttissuesdirecttargetingof SEMA7Acouldhavelowtoxicity.

Public Health Relevance

Wewilltestthehypothesiscollagen,COX-2andSEMA7Apromotebreasttumorcellinvasionandabilityto enhancelymphangiogenesisthroughcooperativemechanismstofacilitatebreasttumormetastasis. MechanismsuncoveredbyourstudieswillprovideimpetusforclinicaltrialstargetingCOX-2and/orSEMA7A aimedatimprovingoutcomesforthousandsofbreastcancerpatientsannually.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA211696-03
Application #
9696353
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Woodhouse, Elizabeth
Project Start
2017-06-19
Project End
2022-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost

  Institution

Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045

  Publications

Elder, Alan M; Tamburini, Beth A J; Crump, Lyndsey S et al. (2018) Semaphorin 7A Promotes Macrophage-Mediated Lymphatic Remodeling during Postpartum Mammary Gland Involution and in Breast Cancer. Cancer Res 78:6473-6485