AR Signaling in Human Malignancies: Prostate Cancer and Beyond Emmanuel S. Antonarakis ...

246 Pages·2017·8.99 MB·English

cancers
AR Signaling
in Human
Malignancies:
Prostate Cancer
and Beyond
Edited by
Emmanuel S. Antonarakis
Printed Edition of the Special Issue Published in Cancers
www.mdpi.com/journal/cancers
AR Signaling in Human Malignancies:
Prostate Cancer and Beyond
Special Issue Editor
Emmanuel S. Antonarakis
MDPI • Basel • Beijing • Wuhan • Barcelona • Belgrade
Special Issue Editor
Emmanuel S. Antonarakis
Johns Hopkins University
USA
Editorial Office
MDPI AG
St. Alban-Anlage 66
Basel, Switzerland
This edition is a reprint of the Special Issue published online in the open access
journal Cancers (ISSN 2072-6694) from 2016–2018 (available at:
http://www.mdpi.com/journal/cancers/special_issues/ar_signal).
For citation purposes, cite each article independently as indicated on the article
page online and as indicated below:
Lastname, F.M.; Lastname, F.M. Article title. Journal Name. Year. Article number,
page range.
First Edition 2018

ISBN 978-3-03842-740-7 (Pbk)
ISBN 978-3-03842-739-1 (PDF)
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Table of Contents
AbouttheSpecialIssueEditor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v
Preface to ”AR Signaling in Human Malignancies: Prostate Cancer and Beyond” . . . . . . . vii
EmmanuelS.Antonarakis
ARSignalinginHumanMalignancies:ProstateCancerandBeyond
doi:10.3390/cancers10010022 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
MichaelT.SchweizerandEvanY.Yu
AR-SignalinginHumanMalignancies:ProstateCancerandBeyond
doi:10.3390/cancers9010007. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
MeganCrumbaker,LeilaKhojaandAnthonyM.Joshua
ARSignalingandthePI3KPathwayinProstateCancer
doi:10.3390/cancers9040034. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
DaisukeObinata,KenichiTakayama,SatoruTakahashiandSatoshiInoue
Crosstalk of the Androgen Receptor with Transcriptional Collaborators: Potential
TherapeuticTargetsforCastration-ResistantProstateCancer
doi:10.3390/cancers9030022. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
KurtisEisermannandGailFraizer
TheAndrogenReceptorandVEGF:MechanismsofAndrogen-RegulatedAngiogenesisin
ProstateCancer
doi:10.3390/cancers9040032. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
DamienA.LeachandGrantBuchanan
StromalAndrogenReceptorinProstateCancerDevelopmentandProgression
doi:10.3390/cancers9010010. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
Vito Cucchiara, Joy C. Yang, Vincenzo Mirone, Allen C. Gao, Michael G. Rosenfeld and
ChristopherP.Evans
Epigenomic Regulation of Androgen Receptor Signaling: Potential Role in Prostate
CancerTherapy
doi:10.3390/cancers9010009. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
HubertPakula,DongxiXiangandZheLi
ATaleofTwoSignals: ARandWNTinDevelopmentandTumorigenesisofProstateand
MammaryGland
doi:10.3390/cancers9020014. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
BilalRahimandRuthORegan
ARSignalinginBreastCancer
doi:10.3390/cancers9030021. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
RameshNarayananandJamesT.Dalton
AndrogenReceptor:AComplexTherapeuticTargetforBreastCancer
doi:10.3390/cancers8120108. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180
iii
Yuka Asano, Shinichiro Kashiwagi, Wataru Goto, Sayaka Tanaka, Tamami Morisaki,
TsutomuTakashima,SatoruNoda,NaoyoshiOnoda,MasahikoOhsawa,KoseiHirakawa
andMasaichiOhira
ExpressionandClinicalSignificanceofAndrogenReceptorinTriple-NegativeBreastCancer
doi:10.3390/cancers9010004. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
PengLi,JinboChenandHiroshiMiyamoto
AndrogenReceptorSignalinginBladderCancer
doi:10.3390/cancers9020020. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
MartinG.Dalin,PhilipA.Watson,AlanL.HoandLucG.T.Morris
AndrogenReceptorSignalinginSalivaryGlandCancer
doi:10.3390/cancers9020017. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
Tatsuo Kanda, Koji Takahashi, Masato Nakamura, Shingo Nakamoto, Shuang Wu,
Yuki Haga, Reina Sasaki, Xia Jiang and Osamu Yokosuka
Androgen Receptor Could Be a Potential Therapeutic Target in Patients with Advanced
Hepatocellular Carcinoma
doi:10.3390/cancers9050043. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229
iv
About the Special Issue Editor
Emmanuel S. Antonarakis is an Associate Professor of Oncology and Urology at the Johns Hopkins
Sidney Kimmel Comprehensive Cancer Center, and the Director of Prostate Cancer Medical Oncology
Research. His work focuses on drug development and clinical trial design for patients with prostate
cancer. More specifically, he is interested in developing novel androgen-directed therapies as well
as immunotherapies for men with recurrent or advanced prostate cancer. He also has an interest
in liquid biomarker development, specifically the clinical validation of the AR-V7 marker as well as
DNA repair markers and their therapeutic implications. He is currently the PI of several phase II and
III prostate cancer trials, and is an active member of the Prostate Cancer Clinical Trials Consortium
(PCCTC) and the Eastern Cooperative Oncology Group (ECOG) as well as the NCI Prostate Cancer
Task Force and the NCCN Prostate Cancer Panel. He is the author of over 175 peer-reviewed articles,
and several book chapters.
v

Preface to ”AR Signaling in Human Malignancies:
Prostate Cancer and Beyond”
The notion that androgens and androgen receptor (AR) signaling are the hallmarks of prostate
cancer oncogenesis and disease progression is generally well accepted. What is more poorly
understood is the role of AR signaling in other human malignancies. This Special Issue of Cancers
initially reviews the role of AR in advanced prostate cancer, and then explores the potential
importance of AR signaling in other epithelial malignancies. The first few articles focus on the use of
novel AR-targeting therapies in castration-resistant prostate cancer and the mechanisms of resistance
to novel antiandro-gens, and they also outline the interaction between AR and other cellular
pathways, including PI3 kinase signaling, transcriptional regulation, angiogenesis, stromal factors,
Wnt signaling, and epige-netic regulation in prostate cancer. The next several articles review the
possible role of androgens and AR signaling in breast cancer, bladder cancer, salivary gland cancer,
and hepatocellular carcinoma, as well as the potential treatment implications of using antiandrogen
therapies in these non-prostatic malignancies.
Emmanuel S. Antonarakis
Special Issue Editor
vii

cancers
Editorial
AR Signaling in Human Malignancies:
Prostate Cancer and Beyond
EmmanuelS.Antonarakis
TheSidneyKimmelComprehensiveCancerCenteratJohnsHopkins,1650OrleansStreet,CRB1–1M45,
Baltimore,MD21287,USA;[email protected];Tel.:[phone]
Received:17January2018;Accepted:17January2018;Published:18January2018
Abstract: Thenotionthatandrogensandandrogenreceptor(AR)signalingarethehallmarksof
prostate cancer oncogenesis and disease progression is generally well accepted. What is more
poorlyunderstoodistheroleofARsignalinginotherhumanmalignancies. Thisspecialissueof
CancersinitiallyreviewstheroleofARinadvancedprostatecancer,andthenexploresthepotential
importanceofARsignalinginotherepithelialmalignancies. Thefirstfewarticlesfocusonthe
useofnovelAR-targetingtherapiesincastration-resistantprostatecancerandthemechanismsof
resistancetonovelantiandrogens,andtheyalsooutlinetheinteractionbetweenARandothercellular
pathways,includingPI3kinasesignaling,transcriptionalregulation,angiogenesis,stromalfactors,
Wntsignaling,andepigeneticregulationinprostatecancer. Thenextseveralarticlesreviewthe
possibleroleofandrogensandARsignalinginbreastcancer,bladdercancer,salivaryglandcancer,
andhepatocellularcarcinoma,aswellasthepotentialtreatmentimplicationsofusingantiandrogen
therapiesinthesenon-prostaticmalignancies.
Androgensandandrogenreceptor(AR)signalingarethehallmarksofprostatecanceroncogenesis
anddiseaseprogression.Whilethemedicalliteratureissaturatedbystudiesexaminingtheroleof
androgens/ARinprostatecancer,lessattentionhasbeengiventothepotentialimportanceoftheAR
pathwayinotherhumanmalignancies.ThegoalofthisspecialissueofCancersistoshedmorelight
ontheclinicalsignificanceofandrogen/ARsignaling,notjustinprostatecancer,butalsoinother
epithelialmalignancies.
ThisthemeissuebeginswithathoughtfulsummarybySchweizeretal.[1]introducingtheAR
signalingfieldinprostaticandothermalignancies. Afterdescribingthebiologicalandtherapeutic
rolesofARinprostatecancer,theauthorsreviewtheevidencesupportingAR-directedtherapies
in other tumor types including breast cancer, bladder cancer, kidney cancer, pancreatic cancer,
hepatocellularcancer,ovarianandendometrialcancers,mantlecelllymphoma,andsalivarygland
cancers.ThisisfollowedbyareviewbyCrumbakeretal.[2]thatsummarizestheinteractionbetween
ARandPI3kinasesignalinginprostatecancer,outlinestheroleofthePI3Kpathwayinprostate
cancer,andreviewsthepotentialclinicalutilityofdualtargetingofARandPI3Kasatherapeutic
strategyinprostatecancer. ThenextreviewbyObinataetal.[3]delvesdeeperintotheinterplay
between AR and other collaborative transcription factors (such as FOXA1, GATA2, and OCT1),
andproposesnewstrategiestoco-targetARtogetherwithsomeofthesetranscriptionalcollaborators,
withparticularattentiontopyrrole–imidazolepolyamideasacandidatecompound.Thisisfollowed
byareviewarticlebyEisermannetal.[4]discussingtheinteractionsbetweenAR,angiogenesis,andthe
vascularendothelialgrowthfactor(VEGF)inprostatecancer,hormone-mediatedmechanismsofVEGF
regulation,andpotentialtherapeuticstrategiesthattakeintoaccountbothARandhypoxiaaspotential
regulatorsofangiogenesis.Thenextarticle,byLeachetal.[5],reviewstheimportantbutunderstudied
subjectofARsignalinginthestromalcompartment(primarilyinfibroblastsandmyofibroblasts)in
thecontextofprostatecancer,suggestingthatstromalARactivitystronglyinfluencesprognosisand
progressionofthisdisease. Thenextarticle,byCucchiaraetal.[6],summarizesourknowledgeof
Cancers 2018,10,22 1 www.mdpi.com/journal/cancers