title: BEX2 is overexpressed in a subset of primary breast cancers and mediates nerve growth factor/nuclear factor-kappaB inhibition of apoptosis in breast cancer cell lines.
abstract: We have identified a novel subtype of estrogen receptor (ER)-positive breast cancers with improved outcome after tamoxifen treatment and characterized by overexpression of the gene BEX2. BEX2 and its homologue BEX1 have highly correlated expression and are part of a cluster enriched for ER response and apoptosis genes. BEX2 expression is induced after estradiol (E2) treatment with a peak at 3 h, suggesting BEX2 is an estrogen-regulated gene. BEX2 belongs to a family of genes, including BEX1, NGFRAP1 (alias BEX3), BEXL1 (alias BEX4), and NGFRAP1L1 (alias BEX5). Both BEX1 and NGFRAP1 interact with p75NTR and modulate nerve growth factor (NGF) signaling through nuclear factor-kappaB (NF-kappaB) to regulate cell cycle, apoptosis, and differentiation in neural tissues. In breast cancer cells, NGF inhibits C2-induced apoptosis through binding of p75NTR and NF-kappaB activation. Here, we show that BEX2 expression is necessary and sufficient for the NGF-mediated inhibition (through NF-kappaB activation) of C2-induced apoptosis. We also show that BEX2 modulates apoptosis of breast cancer cells in response to E2 (50 nmol/L) and tamoxifen (5 and 10 micromol/L). Furthermore, BEX2 overexpression enhances the antiproliferative effect of tamoxifen at pharmacologic dose (1 micromol/L). These data suggest that a NGF/BEX2/NF-kappaB pathway is involved in regulating apoptosis in breast cancer cells and in modulating response to tamoxifen in primary tumors.
authors.affiliation: Cancer Genomics Program, Department of Oncology, University of Cambridge, Hutchison/Medical Research Council Research Center, Hills Road, Cambridge, United Kingdom. an258@cam.ac.uk
authors.forename: Ali
authors.initials: A
authors.lastname: Naderi
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Teschendorff
authors.forename: Juergen
authors.initials: J
authors.lastname: Beigel
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Cariati
authors.forename: Ian O
authors.initials: IO
authors.lastname: Ellis
authors.forename: James D
authors.initials: JD
authors.lastname: Brenton
authors.forename: Carlos
authors.initials: C
authors.lastname: Caldas
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis*; D020411:Oligonucleotide Array Sequence Analysis; D013629:Tamoxifen / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection
chemical_list: D018931:Antineoplastic Agents, Hormonal; D051017:Apoptosis Regulatory Proteins; C469586:BEX1 protein, human; C530662:BEX2 protein, human; C410727:BEX3 protein, human; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D013629:Tamoxifen; D020932:Nerve Growth Factor