title: C-FLIP(L) contributes to TRAIL resistance in HER2-positive breast cancer.
abstract: Breast cancers with HER2 amplification have a poorer prognosis than the luminal phenotypes. TRAIL activates apoptosis upon binding its receptors in some but not all breast cancer cell lines. Herein, we investigated the expression pattern of c-FLIP(L) in a cohort of 251 invasive breast cancer tissues and explored its potential role in TRAIL resistance. C-FLIP(L) was relatively high-expressed in HER2-positive breast cancer in comparison with other molecular subtypes, co-expressed with TRAIL death receptors, and inversely correlated with the apoptosis index. Downregulation of c-FLIP(L) sensitized SKBR3 cells to TRAIL-induced apoptosis in a concentration- and time-dependent manner and enhanced the activities and cleavages of caspase-8 and caspase-3, without altering the surface expression of death receptors. Together, our results indicate that c-FLIP(L) promotes TRAIL resistance and inhibits caspase-3 and caspase-8 activation in HER2-positive breast cancer.
authors.affiliation: Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China.
authors.forename: Fenglin
authors.initials: F
authors.lastname: Zang
authors.affiliation: Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China.
authors.forename: Xiyin
authors.initials: X
authors.lastname: Wei
authors.affiliation: Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Leng
authors.affiliation: Princess Margaret Cancer Centre, University Health Network and University of Toronto, Toronto, Ontario M5G 2M9, Canada.
authors.forename: Man
authors.initials: M
authors.lastname: Yu
authors.affiliation: Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China. Electronic address: baocun_sun@126.com.
authors.forename: Baocun
authors.initials: B
authors.lastname: Sun
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D018719:Erb-b2 Receptor Tyrosine Kinases; D053221:TNF-Related Apoptosis-Inducing Ligand; C506386:CFLAR protein, human; C508053:ERBB2 protein, human
keywords: Apoptosis; C-FLIP(L); HER2-positive breast cancer; TRAIL resistance