Altered Death Receptor Signaling Promotes Epithelial-to-Mesenchymal Transition and Acquired Chemoresistance

• Published in: Scientific reports Vol. 2; no. 1; p. 539
• Main Authors: Antoon, James W., Lai, Rongye, Struckhoff, Amanda P., Nitschke, Ashley M., Elliott, Steven, Martin, Elizabeth C., Rhodes, Lyndsay V., Yoon, Nam Seung, Salvo, Virgilio A., Shan, Bin, Beckman, Barbara S., Nephew, Kenneth P., Burow, Matthew E.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27.07.2012; Nature Publishing Group
• Subjects: 631/67/70; 631/80/82; 631/80/86; 692/420/755; Animals; Apoptosis; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Cell Line, Tumor; Cell Survival - genetics; Cell Transformation, Neoplastic - genetics; Chemoresistance; Chemotherapy; Cluster Analysis; Death; Disease Models, Animal; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition - genetics; Estrogen Receptor alpha - metabolism; Estrogen receptors; Estrogens; Female; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humanities and Social Sciences; Humans; Mesenchyme; Mice; Mice, Nude; multidisciplinary; Multidrug resistance; NF-kappa B - metabolism; NF-κB protein; Receptors, Death Domain; Receptors, Tumor Necrosis Factor - metabolism; Science; Signal Transduction; Tumor necrosis factor; Tumor Necrosis Factor-alpha - pharmacology; Tumor Necrosis Factor-alpha - toxicity; Tumor necrosis factor-TNF; Xenograft Model Antitumor Assays
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep00539

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.