title: Altered death receptor signaling promotes epithelial-to-mesenchymal transition and acquired chemoresistance.
abstract: Altered death receptor signaling and resistance to subsequent apoptosis is an important clinical resistance mechanism. Here, we investigated the role of death receptor resistance in breast cancer progression. Resistance of the estrogen receptor alpha (ER)-positive, chemosensitive MCF7 breast cancer cell line to tumor necrosis factor (TNF) was associated with loss of ER expression and a multi-drug resistant phenotype. Changes in three major pathways were involved in this transition to a multidrug resistance phenotype: ER, Death Receptor and epithelial to mesenchymal transition (EMT). Resistant cells exhibited altered ER signaling, resulting in decreased ER target gene expression. The death receptor pathway was significantly altered, blocking extrinsic apoptosis and increasing NF-kappaB survival signaling. TNF resistance promoted EMT changes, resulting in a more aggressive phenotype. This first report identifying specific mechanisms underlying acquired resistance to TNF could lead to a better understanding of the progression of breast cancer in response to chemotherapy treatment.
authors: Departments of Pharmacology, Tulane University School of Medicine, Tulane Avenue, New Orleans, LA, USA.
authors: James W
authors: JW
authors: Antoon
authors: Rongye
authors: R
authors: Lai
authors: Amanda P
authors: AP
authors: Struckhoff
authors: Ashley M
authors: AM
authors: Nitschke
authors: Steven
authors: S
authors: Elliott
authors: Elizabeth C
authors: EC
authors: Martin
authors: Lyndsay V
authors: LV
authors: Rhodes
authors: Nam Seung
authors: NS
authors: Yoon
authors: Virgilio A
authors: VA
authors: Salvo
authors: Bin
authors: B
authors: Shan
authors: Barbara S
authors: BS
authors: Beckman
authors: Kenneth P
authors: KP
authors: Nephew
authors: Matthew E
authors: ME
authors: Burow
mesh_terms: D000818:Animals; D017209:Apoptosis; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D016000:Cluster Analysis; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism; D053218:Receptors, Death Domain; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000633:toxicity; D023041:Xenograft Model Antitumor Assays
chemical_list: D047628:Estrogen Receptor alpha; D016328:NF-kappa B; D053218:Receptors, Death Domain; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha