Abstract

Anti-steroidtherapyisstandardofcaretherapyforbothER+breastcancerandforprostatecancer.Both cancersmetastasizepredominantlytobone.Estrogensandandrogensarealsokeymediatorsofnormalbone growth,homeostasis,andmaintenanceoftheosteogenicnicheinbothfemalesandmales.Bothcancers metastasizetotheosteogenic/hematopoieticnicheintrabecularbone.Accordingly,theearlystagebone colonizationofprostateandER+breastcancermayinvolvesimilarosteogeniccell-dependentmechanisms. TheosteoprogenitorandosteoblastsintheosteogenicnicheareregulatedprimarilybyER?andARactionsin bothgenders.Deficienciesthesereceptorsoftentranslateintoseverepathologicalboneconditions.Thus,any anti-steroidtherapiestargetingprostateandER+breastcancerswillalsoinevitablyaffectthe microenvironment,i.e.,theosteogenicnichecells.However,thereisalackofunderstandingofhowanti- steroidtherapiesaffectthebiologyofosteogenicnichecells,andhowthisaffectscancerprogressionand evolutiontotherapeuticresistance.TheZhangandRowleylaboratorieshavebothdevelopednovel3D osteogenicheterotypicalorganoidmodelsthataddresseshumanbreastandprostatecancercellsinteraction withhumanosteogeniccellsrespectively.Moreover,novelintra-iliacarteryinjectionandmousecalvaria intravitalimagingmodelshavepermittedthestudyofdirectinteractionswiththeosteogenicnicheintrabecular boneinvivo.Preliminarydatasuggestsanti-steroidtherapymayresultinarepairphenotypeintheosteogenic nichethatmaypromotecancerprogressionandtherapeuticresistance.Hence,itisourhypothesisthatanti- steroidtherapyaffectstheosteogenicnichetoamorehomeostasis-repairphenotypethatiscancer-promoting. Toaddressthis,weproposetwoSpecificAims.
SpecificAim1. Toaddressboneosteogenicniche-cancer interactionsindifferentialsteroidandanti-steroidactionconditionsusingnovel3Dosteogenicorganoid approaches.
This Aim willaddresstherelativeimportanceofER?,ER?,andARinmediatingestrogen, androgen,andanti-steroidactionsinthegenesisofareactiveosteogenicniche,howitaffectsbreastand prostatecancerbiology,andhowitaltersanti-steroidtherapeuticefficacies.
SpecificAim2. Toaddress mechanismsofanti-steroid(estrogenandandrogen)biologyintheosteogenicnicheandhowthisaffects colonyinitiationandprogressionofbreastandprostatecancerinvivo.Usinggeneticallyengineeredmouse models,noveltumortransplantationapproachesandcutting-edgeintravitalmicroscopy,wewillexaminethe impactofanti-steroidtreatmentsontheosteogenicnicheinvivoandhowitleadstoendocrineresistance.The overallgoalofthismulti-PIproposalistoidentifycommonmechanismsofosteogenicnichebiologythataffects theevolutionofbreastandprostatemetastaticprogressionduringanti-steroidtherapy.Thesepathwaysmay representtargetsfornoveltherapeuticapproaches.

Public Health Relevance

Theefficacyofanti-steroidtherapyforER+breastandprostatecancercanbeimprovedbyunderstanding themechanismsofhowthesetherapiesaffecttheosteogenicnichemicroenvironmentinbone. Mechanismsarenotunderstood.Understandingmechanismscanleadtonewtherapeuticapproachesto targettheosteogenicnichetumormicroenvironmenttoimproveefficacyoftherapyformetastaticbreastand prostatecancer.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA221946-03
Application #
10001465
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Ault, Grace S
Project Start
2018-09-05
Project End
2023-08-31
Budget Start
2020-09-01
Budget End
2021-08-31
Support Year
3
Fiscal Year
2020
Total Cost
Indirect Cost

  Institution

Name
Baylor College of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030