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dc.contributor.authorNagalingam, Arumugam
dc.contributor.authorSiddharth, Sumit
dc.contributor.authorParida, Sheetal
dc.contributor.authorMuniraj, Nethaji
dc.contributor.authorAvtanski, Dimiter
dc.contributor.authorKuppusamy, Panjamurthy
dc.contributor.authorElsey, Justin
dc.contributor.authorArbiser, Jack L
dc.contributor.authorGyőrffy, Balázs
dc.contributor.authorSharma, Dipali
dc.date.accessioned2021-08-18T12:52:26Z
dc.date.available2021-08-18T12:52:26Z
dc.date.issued2021-08-13
dc.identifier.urihttp://hdl.handle.net/10713/16407
dc.description.abstractObese women with hormone receptor-positive breast cancer exhibit poor response to therapy and inferior outcomes. However, the underlying molecular mechanisms by which obesity/hyperleptinemia may reduce the efficacy of hormonal therapy remain elusive. Obese mice with hyperleptinemia exhibit increased tumor progression and respond poorly to tamoxifen compared to non-obese mice. Exogenous leptin abrogates tamoxifen-mediated growth inhibition and potentiates breast tumor growth even in the presence of tamoxifen. Mechanistically, leptin induces nuclear translocation of phosphorylated-ER and increases the expression of ER-responsive genes, while reducing tamoxifen-mediated gene repression by abrogating tamoxifen-induced recruitment of corepressors NCoR, SMRT, and Mi2 and potentiating coactivator binding. Furthermore, in silico analysis revealed that coactivator Med1 potentially associates with 48 (out of 74) obesity-signature genes. Interestingly, leptin upregulates Med1 expression by decreasing miR-205, and increases its functional activation via phosphorylation, which is mediated by activation of Her2 and EGFR. It is important to note that Med1 silencing abrogates the negative effects of leptin on tamoxifen efficacy. In addition, honokiol or adiponectin treatment effectively inhibits leptin-induced Med1 expression and improves tamoxifen efficacy in hyperleptinemic state. These studies uncover the mechanistic insights how obese/hyperleptinemic state may contribute to poor response to tamoxifen implicating leptin-miR205-Med1 and leptin-Her2-EGFR-Med1 axes, and present bioactive compound honokiol and adipocytokine adiponectin as agents that can block leptin's negative effect on tamoxifen.en_US
dc.description.urihttps://doi.org/10.1038/s41523-021-00314-9en_US
dc.language.isoenen_US
dc.publisherSpringer Natureen_US
dc.relation.ispartofNPJ Breast Canceren_US
dc.rights© 2021. The Author(s).en_US
dc.subjecthormone receptor-positive breast canceren_US
dc.subjecthyperleptinemiaen_US
dc.subject.meshLeptinen_US
dc.subject.meshObesityen_US
dc.subject.meshTamoxifen--antagonists & inhibitorsen_US
dc.titleHyperleptinemia in obese state renders luminal breast cancers refractory to tamoxifen by coordinating a crosstalk between Med1, miR205 and ErbBen_US
dc.typeArticleen_US
dc.identifier.doi10.1038/s41523-021-00314-9
dc.identifier.pmid34389732
dc.source.volume7
dc.source.issue1
dc.source.beginpage105
dc.source.endpage
dc.source.countryUnited States


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