title: Eph receptor B4 is a regulator of estrogen receptor alpha in breast cancer cells.
abstract: BACKGROUND
  Estrogen receptor alpha (ER-α) plays an important role in breast cancer initiation and progression and represents a major target in cancer therapy. The expression and activity of ER-α is regulated by multiple mechanisms at the transcriptional and post-translational level. Interaction of tyrosine kinase receptor-activated signaling pathways with ER-α function has been reported. We previously performed a kinome-wide small interfering RNA high-throughput screen to identify novel protein kinases involved in the regulation of ER-α transcriptional activity in human breast cancer cells. Our screening analysis identified the Eph receptor tyrosine kinases (Eph) as potential positive regulators of ER-α.
  
  
  RESULTS
  In this study, we demonstrate Eph receptor B4 (EphB4), a member of Eph kinase family, a positive regulator of ER-α in human breast cancer cell lines (MCF-7, T-47D and BT-474). Down-regulation of EphB4 by RNA interference technology impairs estrogen-dependent ER-α transcriptional activity in breast cancer cells. Decreased activity of ER-α after EphB4 knockdown is the consequence of diminished ER-α messenger RNA and protein expression. Furthermore, phosphorylation of Akt, a downstream mediator of EphB4, is reduced following EphB4 silencing.
  
  
  CONCLUSIONS
  Our data suggests EphB4 as an upstream regulator of ER-α in human breast cancer cells by modulating ER-α transcription. The results also suggest Akt as a relevant downstream signaling molecule in this novel EphB4-ER-α pathway.
authors.affiliation: Hormones and Signal Transduction Group, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Fee
authors.initials: F
authors.lastname: Schmitt
authors.forename: Phuong-Hien
authors.initials: PH
authors.lastname: Nguyen
authors.forename: Nibedita
authors.initials: N
authors.lastname: Gupta
authors.forename: Doris
authors.initials: D
authors.lastname: Mayer
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D036081:Receptors, Eph Family / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D047628:Estrogen Receptor alpha; D034741:RNA, Small Interfering; D036081:Receptors, Eph Family; D051057:Proto-Oncogene Proteins c-akt