Crosstalk between PKCalpha and Notch-4 in endocrine-resistant breast cancer cells Journal Article

Authors: Yun, J; Pannuti, A.; Espinoza, I.; Zhu, H; Hicks, C.; Zhu, X; Caskey, M.; Rizzo, P.; D'Souza, G.; Backus, K.; Denning, M. F.; Coon, J.; Sun, M.; Bresnick, E. H.; Osipo, C; Wu, J; Strack, P. R.; Tonetti, D. A.; Miele, L
Article Title: Crosstalk between PKCalpha 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 alpha (ERalpha)+ 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 Calpha (PKCalpha) overexpression is common in endocrine-resistant breast cancers and promotes tamoxifen (TAM)-resistant growth in breast cancer cell lines. We tested whether PKCalpha overexpression affects Notch activity and whether Notch signaling contributes to endocrine resistance in PKCalpha-overexpressing breast cancer cells.Analysis of published microarray data from ERalpha+ breast carcinomas shows that PKCalpha expression correlates strongly with Notch-4. Real-time reverse transcription PCR and immunohistochemistry on archival specimens confirmed this finding. In a PKCalpha-overexpressing, TAM-resistant T47D model, PKCalpha 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 PKCalpha-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 PKCalpha-expressing T47D cells. In PKCalpha-overexpressing T47D xenografts, an orally active gamma-secretase inhibitor at clinically relevant doses significantly decreased estrogen-independent tumor growth, alone and in combination with TAM. In conclusion, PKCalpha 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 PKCalpha- and Notch-4-overexpressing, endocrine-resistant breast cancers.
Journal Title: Oncogenesis
Volume: 2
ISSN: 2157-9024; 2157-9024
Publisher: Unknown  
Journal Place: United States
Date Published: 2013
Start Page: e60
Language: eng
Notes: LR: 20140113; JID: 101580004; OID: NLM: PMC3759125; 2012/04/11 [received]; 2013/06/14 [revised]; 2013/06/19 [accepted]; epublish