Activating transcription factor 4 modulates TGFβ-induced aggressiveness in triple negative breast cancer via SMAD2/3/4 and mTORC2 signaling

Based on the identified stress-independent cellular functions of activating transcription factor 4 (ATF4), we reported enhanced ATF4 levels in MCF10A cells treated with TGFβ1. ATF4 is overexpressed in triple negative breast cancer (TNBC) patients, but its impact on patient survival and the underlyin...

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Published in:	Clinical cancer research 2018-11, Vol.24 (22), p.5697-5709
Main Authors:	González-González, Adrián, Muñoz-Muela, Esperanza, Marchal, Juan A, Cara, Francisca Elvira, Molina, Maria Pilar, Cruz-Lozano, Marina, Jiménez, Gema, Verma, Akanksha, Ramírez, Alberto, Qian, Wei, Chen, Wen, Kozielski, Anthony J, Elemento, Olivier, Martin-Salvago, M Dolores, Luque, Rafael Jesús, Rosa-Garrido, Carmen, Landeira, David, Quintana-Romero, María, Rosato, Roberto R, García, María A, Ramírez-Tortosa, César L, Kim, Hanna, Rodriguez-Aguayo, Cristian, Lopez-Berestein, Gabriel, Sood, Anil K, Lorente, José A, Sánchez-Rovira, Pedro, Chang, Jenny C, Granados-Principal, Sergio
Format:	Article
Language:	eng
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Summary:	Based on the identified stress-independent cellular functions of activating transcription factor 4 (ATF4), we reported enhanced ATF4 levels in MCF10A cells treated with TGFβ1. ATF4 is overexpressed in triple negative breast cancer (TNBC) patients, but its impact on patient survival and the underlying mechanisms remain unknown. We aimed to determine effects on breast cancer patient survival and TNBC aggressiveness, and the relationships between TGFβ and ATF4. Defining the signaling pathways may help us identify a cell signaling-tailored gene signature. Patient survival data was determined by Kaplan-Meier analysis. Relationship between TGFβ and ATF4, their effects on aggressiveness (tumor proliferation, metastasis, and stemness), and the underlying pathways were analyzed in three TNBC cell lines and using patient-derived xenografts (PDXs). overexpression correlated with TNBC patient survival decrease and a SMAD-dependent crosstalk between ATF4 and TGFβ was identified. expression inhibition reduced migration, invasiveness, mammosphere-forming efficiency, proliferation, epithelial-mesenchymal transition, and antiapoptotic and stemness marker levels. In PDX models, silencing decreased metastases, tumor growth, and relapse after chemotherapy. ATF4 was shown to be active downstream of SMAD2/3/4 and mTORC2, regulating TGFβ/SMAD and mTOR/RAC1-RHOA pathways independently of stress. We defined an eight-gene signature with prognostic potential, altered in 45% of 2509 breast cancer patients. ATF4 may represent a valuable prognostic biomarker and therapeutic target in TNBC patients, and we identified a cell-signaling pathway-based gene signature that may contribute to the development of combinatorial targeted therapies for breast cancer.
ISSN:	1078-0432 1557-3265