title: Crosstalk between PKCα and Notch-4 in endocrine-resistant breast cancer cells.
abstract: The Notch pathway is functionally important in breast cancer. Notch-1 has been reported to maintain an estrogen-independent phenotype in estrogen receptor α (ERα)+ breast cancer cells. Notch-4 expression correlates with Ki67. Notch-4 also plays a key role in breast cancer stem-like cells. Estrogen-independent breast cancer cell lines have higher Notch activity than estrogen-dependent lines. Protein kinase Cα (PKCα) overexpression is common in endocrine-resistant breast cancers and promotes tamoxifen (TAM)-resistant growth in breast cancer cell lines. We tested whether PKCα overexpression affects Notch activity and whether Notch signaling contributes to endocrine resistance in PKCα-overexpressing breast cancer cells.Analysis of published microarray data from ERα+ breast carcinomas shows that PKCα expression correlates strongly with Notch-4. Real-time reverse transcription PCR and immunohistochemistry on archival specimens confirmed this finding. In a PKCα-overexpressing, TAM-resistant T47D model, PKCα selectively increases Notch-4, but not Notch-1, expression in vitro and in vivo. This effect is mediated by activator protein-1 (AP-1) occupancy of the Notch-4 promoter. Notch-4 knockdown inhibits estrogen-independent growth of PKCα-overexpressing T47D cells, whereas Notch-4IC expression stimulates it. Gene expression profiling shows that multiple genes and pathways associated with endocrine resistance are induced in Notch-4IC- and PKCα-expressing T47D cells. In PKCα-overexpressing T47D xenografts, an orally active γ-secretase inhibitor at clinically relevant doses significantly decreased estrogen-independent tumor growth, alone and in combination with TAM. In conclusion, PKCα overexpression induces Notch-4 through AP-1. Notch-4 promotes estrogen-independent, TAM-resistant growth and activates multiple pathways connected with endocrine resistance and chemoresistance. Notch inhibitors should be clinically evaluated in PKCα- and Notch-4-overexpressing, endocrine-resistant breast cancers.
authors.affiliation: Cardinal Bernardin Cancer Center and Department of Pathology, Loyola University Chicago, Maywood, IL, USA.
authors.forename: J
authors.initials: J
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authors.forename: A
authors.initials: A
authors.lastname: Pannuti
authors.forename: I
authors.initials: I
authors.lastname: Espinoza
authors.forename: H
authors.initials: H
authors.lastname: Zhu
authors.forename: C
authors.initials: C
authors.lastname: Hicks
authors.forename: X
authors.initials: X
authors.lastname: Zhu
authors.forename: M
authors.initials: M
authors.lastname: Caskey
authors.forename: P
authors.initials: P
authors.lastname: Rizzo
authors.forename: G
authors.initials: G
authors.lastname: D'Souza
authors.forename: K
authors.initials: K
authors.lastname: Backus
authors.forename: M F
authors.initials: MF
authors.lastname: Denning
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authors.initials: J
authors.lastname: Coon
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authors.lastname: Sun
authors.forename: E H
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authors.initials: PR
authors.lastname: Strack
authors.forename: D A
authors.initials: DA
authors.lastname: Tonetti
authors.forename: L
authors.initials: L
authors.lastname: Miele
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