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Manzoor Ahmad Mir Editor Therapeutic Potential of Cell Cycle Kinases in Breast Cancer Therapeutic Potential of Cell Cycle Kinases in Breast Cancer Manzoor Ahmad Mir Editor Therapeutic Potential of Cell Cycle Kinases in Breast Cancer Editor ManzoorAhmadMir DepartmentofBioresources UniversityofKashmir Srinagar,JammuandKashmir,India ISBN978-981-19-8910-0 ISBN978-981-19-8911-7 (eBook) https://doi.org/10.1007/978-981-19-8911-7 #TheEditor(s)(ifapplicable)andTheAuthor(s),underexclusivelicensetoSpringerNatureSingapore PteLtd.2023 Thisworkissubjecttocopyright.AllrightsaresolelyandexclusivelylicensedbythePublisher,whether thewholeorpartofthematerialisconcerned,specificallytherightsoftranslation,reprinting,reuseof illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similarordissimilarmethodologynowknownorhereafterdeveloped. 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The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore This Book is Dedicated to my Family Ayzel Manzoor Mir Aariz Manzoor Mir Sumaira Manzoor Mir Foreword IampleasedtoprovidetheforewordtoDr.ManzoorAhmadMir’svaluablebook, Therapeutic Potential of Cell Cycle Kinases in Breast Cancer. Breast cancer is a dreadful disease that causes physical and mental suffering to individuals who are diagnosedwithit.Despitehugeinvestmentsinbreastcancertreatment,thenumber of new cases and deaths continues to rise. As per the GLOBOCON 2021 report, breast cancer is the second most prevalent cancer diagnosed in women after skin cancer.Breastcancercanstrikebothmenandwomen,and1among8infemalesand 1 among 1000 in males can get affected. The rate of incidence of breast cancer is more than 1.3 million on a yearly basis. BC can be cured in almost 70–80% of patientshavingearly-stage,non-metastaticBC. The cell cycle is controlled by various cyclins and Cyclin-Dependent Kinases (CDKs). The importance of cyclins and CDKs in the cell cycle was revealed in a study offissionyeast andcelldivision, inwhichthesignificanceofcomplex Cdc2 (CDK1) was geneticallystudiedandexhibitedaneffective role inmitosis.Dr. Mir discussescriticalissuesabouttheincidence,dysregulationofCDKsinbreastcancer, treatment, and prevention of breast cancer using CDK inhibitors. The book has particularly highlighted the conventional as well as the newly developed treatment approaches including various CDK inhibitors in breast cancer. In this regard, the newinnovativetreatmentmethod,especiallythetargetedtherapies,CDKinhibitors, and the nanotechnology intervention approaches, has revolutionized the field of breastcancer. Thus,targetingCDKswiththeirspecificinhibitorsinBCisconsideredtobevery useful. In this book, Dr. Mir has shed light on the role of cell cycle in cancer progression,roleofCDKsandtheirdysregulationinbreastcancer,theirimportance in BC progression and metastasis, their prognostic significance, and the specific CDKinhibitorsusedtoovercometheBCprogression. DepartmentofMedicalLaboratory RaidSaleemAlbaradie MajmaahUniversity AlMajma’ah,SaudiArabia vviiii Preface As per the GLOBOCON 2021 report breast cancer is the second most prevalent cancerdiagnosedinwomenafterskincancer.Breastcancercanstrikebothmenand women,and1among8infemalesand1among1000inmalescangetaffected.The rateofincidenceofbreastcancerismorethan1.3milliononayearlybasis.BCcan becuredinalmost70–80%ofpatientshavingearly-stage,non-metastaticBC.Inthis book,wewillshedlightontheroleofcellcycleincancerprogression,roleofcyclin- dependentkinases(CDKs)andtheirdysregulationinbreastcancer,theirimportance in BC progression and metastasis, their prognostic significance, and the specific CDKinhibitorsusedtoovercometheBCprogression.Amongthevarioushallmarks ofcancer,increasedcellproliferationisoneofthemostimportantaspectsthatneed tobetakenintoconsideration.Theproliferationofcellsissynchronizedbythecell cycle,andtherearewell-definedregulatorymechanismsthatregulatethecellcycle. ThecellcycleiscontrolledbyvariouscyclinsandCDKs.Theimportanceofcyclins andCDKsinthecellcyclewasrevealedinastudyoffissionyeastandcelldivision, in which the significance of complex Cdc2 (CDK1) was genetically studied and exhibitedaneffectiverole inmitosis. CDKsbelongtotheserine-threoninekinases thatcanformanassociationwithcyclins,phosphorylatethemandthusactivatethem at specific positions during the cell cycle progression. The cell division during an individual’s life span as well as during development takes place only at specific placesaswellasaspecifictimeanddividesthecontentofthecellinaveryaccurate way.Thecoherence,integrityaswellasmaintenanceofeverystepinthecellcycle are well maintained by the cell cycle checkpoints. Breast cancer like many other cancersinvolvesincreasedproliferationofcells,whichresultsfromthedisruptionin the cell cycle regulation by dysregulated CDKs. The dysregulation in the CDKs during BC leads to the uncontrolled proliferation of cancer cells, thus maintaining theprogressionofBCalongwithotherfactors.ThestudieshaverevealedthatBCis associatedwithdysregulation ofvariouscyclin/CDKsandtheirdysregulationdoes havearoleindevelopingdifferentphenotypesofBC. In this book, Dr. Mir has discussed critical issues about the incidence, dysregulationofCDKsinbreastcancer,treatment,andpreventionofbreastcancer using CDK inhibitors. The book has particularly highlighted the conventional as wellasthenewlydevelopedtreatmentapproachesincludingvariousCDKinhibitors inbreastcancer.Inthisregard,thenewinnovativetreatmentmethod,especiallythe ix x Preface targetedtherapies,CDKinhibitors,andthenanotechnologyinterventionapproaches, hasrevolutionizedthefieldofbreastcancer.Inthisbook,wewillshedlightonthe role of cell cycle in cancer progression, role of CDKs and their dysregulation in breast cancer, their importance in BC progression and metastasis, their prognostic significance,andthespecificCDKinhibitorsusedtoovercometheBCprogression. Srinagar,JammuandKashmir,India ManzoorAhmadMir Acknowledgments “Firstandforemost,IwouldliketothankthePrimeMoverAlmightyinwhomIhave greatfaith.” Althoughitisdifficulttothankeverybodyandinterweaveinwordsthegenuine effortsmadebythepeopledirectlyorindirectlytomakethisbookpossible,Iwould like to take this opportunity to pen down my appreciation for a great number of people whose contribution in numerous ways immensely helped me to move towards my destination. It gives me immense pleasure to express my sense of gratitude and respect to my mentor Dr. Javed Naim Agrewala, whose constant support, utmost patience, invaluable advice, and guidance rekindled my interest in sciencefromtimetotime.Iwillbenefitforalongtimetocomefromhissincerity, originality,andtruthfulness,whichhasnourishedmyintellectualmaturity.Aspecial voteofthanksgoestoProf.TalatAhmadandProf.NeolofarKhanfortheirefficient guidancetoworkhardwithsincerity,dedication,anddevotionbothinprofessional and personal life. The staff, scholars Mr. Umar Mehraj, Mr. Basharat, Mr. Bashir, Mr.Wajahat,MissHinaQayoom,MissHafsaQadri,MissShaziaSofi,MissShariqa Jan, and the students at the Department of Bioresources deserve a special mention forallthehelprenderedatthehourofneed. I am also thankful to my soulmate Miss Sumaira Manzoor and my parents Mohammad Abdullah Mir, Zoona Begum and my in laws Mohd Ashraf Malik, and Posha Begum for their constant support, love, and care throughout the whole journey.Iwouldliketomentionheretheaffectionandloveshoweredbymyangels AyzelManzoorandAarizManzoorthroughoutthewritingprocessofthebook.Iam shortofwordstojustifytheircare,affection,anduntiringsupportshoweredbythese verygoodfriends. Finally,theauthorwouldliketothankandacknowledgetheJammuandKashmir ScienceTechnologyandInnovationCouncil(JKST&IC)forprovidingthefinancial support vide Project No. JKST&IC/SRE/885-87, dated 27-10-2021 sanctioned to Dr.ManzoorAhmadMir(PrincipalInvestigator),andthisbookispartofthesame project entitled “Targeting Drug Resistant Cancer Stem Cells by Combinational DeliveryofPaclitaxelandQuercetinZerumboneinBreastCancer.” Dr.ManzoorAMir xxii Contents 1 IntroductiontoBreastCancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 ManzoorAhmadMirandHinaQayoom 2 CurrentTreatmentApproachestoBreastCancer. . . . . . . . . . . . . . 23 ManzoorAhmadMirandAbrarYousufMir 3 IntroductiontoCellCycleandItsRegulators. . . . . . . . . . . . . . . . . 53 ManzoorAhmadMirandAsmaJan 4 CellCycleandCancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 ManzoorAhmadMirandShaziaSofi 5 CellCycleDysregulationinBreastCancer. . . . . . . . . . . . . . . . . . . 103 ManzoorAhmadMir,SameerUllahKhan,andShariqaAisha 6 MolecularSubtypesofBreastCancerandCDkDysregulation. . . . 133 ManzoorAhmadMirandIfshanaMohiUdDin 7 BreastTumorMicroenvironmentandCDKs. . . . . . . . . . . . . . . . . 149 ManzoorAhmadMirandAbrarYousufMir 8 CDKDysregulationinBreastCancer:ABioinformaticsAnalysis. . 175 ManzoorAhmadMir,ShaziaSofi,andPirM.Ishfaq 9 CDK1DysregulationinBreastCancer. . . . . . . . . . . . . . . . . . . . . . 195 ManzoorAhmadMirandBurhanUlHaq 10 Cdk4/Cdk6DysregulationinEstrogen-PositiveReceptorBreast Cancers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211 ManzoorAhmadMirandUlfatJan 11 TherapeuticImplicationsofCDKsinBreastCancer. . . . . . . . . . . . 233 ManzoorAhmadMirandBurhanUlHaq 12 NovelCDKInhibitorsinBreastCancer. . . . . . . . . . . . . . . . . . . . . 253 ManzoorAhmadMirandTabishJaveed xxiiiiii