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Development of Dl1.72, a Novel Anti-DLL1 Antibody with Anti-Tumor Efficacy against Estrogen Receptor-Positive Breast Cancer

2021Journal article Open access
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dc.contributor.authorSilva, G
dc.contributor.authorSales-Dias, J
dc.contributor.authorCasal, D
dc.contributor.authorAlves, S
dc.contributor.authorDomenici, G
dc.contributor.authorBarreto, C
dc.contributor.authorMatos, C
dc.contributor.authorLemos, AR
dc.contributor.authorMatias, AT
dc.contributor.authorKucheryava, K
dc.contributor.authorFerreira, A
dc.contributor.authorMoita, MR
dc.contributor.authorBraga, S
dc.contributor.authorBrito, C
dc.contributor.authorCabral, MG
dc.contributor.authorCasalou, C
dc.contributor.authorBarral, DC
dc.contributor.authorSousa, PM
dc.contributor.authorVideira, PA
dc.contributor.authorBandeiras, TM
dc.contributor.authorBarbas, A
dc.date.accessioned2021-09-28T20:49:41Z
dc.date.available2021-09-28T20:49:41Z
dc.date.issued2021
dc.description.abstractAberrant Notch signaling is implicated in several cancers, including breast cancer. However, the mechanistic details of the specific receptors and function of ligand-mediated Notch signaling that promote breast cancer remains elusive. In our studies we show that DLL1, a Notch signaling ligand, is significantly overexpressed in ERα+ luminal breast cancer. Intriguingly, DLL1 overexpression correlates with poor prognosis in ERα+ luminal breast cancer, but not in other subtypes of breast cancer. In addition, this effect is specific to DLL1, as other Notch ligands (DLL3, JAGGED1, and JAGGED2) do not influence the clinical outcome of ERα+ patients. Genetic studies show that DLL1-mediated Notch signaling in breast cancer is important for tumor cell proliferation, angiogenesis, and cancer stem cell function. Consistent with prognostic clinical data, we found the tumor-promoting function of DLL1 is exclusive to ERα+ luminal breast cancer, as loss of DLL1 inhibits both tumor growth and lung metastasis of luminal breast cancer. Importantly, we find that estrogen signaling stabilizes DLL1 protein by preventing its proteasomal and lysososmal degradations. Moreover, estrogen inhibits ubiquitination of DLL1. Together, our results highlight an unexpected and novel subtype-specific function of DLL1 in promoting luminal breast cancer that is regulated by estrogen signaling. Our studies also emphasize the critical role of assessing subtype-specific mechanisms driving tumor growth and metastasis to generate effective subtype-specific therapeutics.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationCancers (Basel) . 2021 Aug 13;13(16):4074.pt_PT
dc.identifier.doi10.3390/cancers13164074pt_PT
dc.identifier.urihttp://hdl.handle.net/10400.26/37598
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.relationA designar
dc.relationApplied Molecular Biosciences Unit
dc.relationApplied Molecular Biosciences Unit
dc.subjectNeoplasias da Mamapt_PT
dc.subjectEstrogéniospt_PT
dc.subjectPeptídeos e Proteínas de Sinalização Intercelularpt_PT
dc.subjectBreast Neoplasmspt_PT
dc.subjectEstrogenspt_PT
dc.subjectIntercellular Signaling Peptides and Proteinspt_PT
dc.titleDevelopment of Dl1.72, a Novel Anti-DLL1 Antibody with Anti-Tumor Efficacy against Estrogen Receptor-Positive Breast Cancerpt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleA designar
oaire.awardTitleApplied Molecular Biosciences Unit
oaire.awardTitleApplied Molecular Biosciences Unit
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/OE/PD%2FBD%2F113987%2F2015/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F04378%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FBBB-BMD%2F4497%2F2014/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDP%2F04378%2F2020/PT
oaire.citation.issue16pt_PT
oaire.citation.startPage4074pt_PT
oaire.citation.titleCancerspt_PT
oaire.citation.volume13pt_PT
oaire.fundingStreamOE
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream3599-PPCDT
oaire.fundingStream6817 - DCRRNI ID
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isProjectOfPublication42b002b7-8160-4acf-8531-a6f5322622f2
relation.isProjectOfPublication3629d929-926b-4c4f-8fe1-25c5dfe39b30
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relation.isProjectOfPublication.latestForDiscoverya565de53-628f-4345-89f1-8468dfc552e6

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