Abstract
Purpose: On the basis of 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 patients with triple-negative breast cancer (TNBC), but its impact on patient survival and the underlying mechanisms remain unknown. We aimed to determine ATF4 effects on patients with breast cancer 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.Experimental Design: Patient survival data were 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 in vivo using patient-derived xenografts (PDX).Results: ATF4 overexpression correlated with TNBC patient survival decrease and a SMAD-dependent crosstalk between ATF4 and TGFβ was identified. ATF4 expression inhibition reduced migration, invasiveness, mammosphere-forming efficiency, proliferation, epithelial-mesenchymal transition, and antiapoptotic and stemness marker levels. In PDX models, ATF4 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 2,509 patients with breast cancer.Conclusions: ATF4 may represent a valuable prognostic biomarker and therapeutic target in patients with TNBC, and we identified a cell signaling pathway-based gene signature that may contribute to the development of combinatorial targeted therapies for breast cancer. Clin Cancer Res; 24(22); 5697-709. ©2018 AACR.
Highlights
Breast cancer is the most commonly diagnosed type of cancer in women and it is associated with high incidence and death rates [1, 2]
activating transcription factor 4 (ATF4) may represent a valuable prognostic biomarker and therapeutic target in patients with Triple-negative breast cancer (TNBC), and we identified a cell signaling pathway–based gene signature that may contribute to the development of combinatorial targeted therapies for breast cancer
Because TNBC microenvironment is often enriched in TGFb ligands [31], we analyzed TGFb activation effects on ATF4 expression, and demonstrated that it increases in BT549 and SUM159PT cells treated with TGFb1, which was abrogated by the TGFbR1 kinase inhibitor LY2157299 treatment (P < 0.001; Fig. 1D), suggesting that ATF4 represents its downstream target
Summary
Breast cancer is the most commonly diagnosed type of cancer in women and it is associated with high incidence and death rates [1, 2]. TNBC is characterized by high proliferation, heterogeneity, metastases, drug resistance, and incidence of relapse, and enriched in aggressiveness-related signaling pathways such as TGFb or mTOR. New. Medicine Institute (IBIMER), Centre for Biomedical Research (CIBM), University of Granada, Granada, Spain. Complejo Hospitalario de Jaen, Servicio Andaluz de Salud, Jaen, Spain. Complejo Hospitalario de Jaen, Servicio Andaluz de Salud, Jaen, Spain. 9Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, University of Granada, Granada, Spain. 10Department of Oncology, Virgen de las Nieves University Hospital, Granada, Spain. 11Texas Tech University Health Sciences Center, School of Pharmacy, Amarillo, Texas. 12Center for RNA
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