Activating Transcription Factor 4 Modulates TGFβ-Induced Aggressiveness in Triple-Negative Breast Cancer via SMAD2/3/4 and mTORC2 Signaling

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Adrián González-GonzálezSergio Granados-Principal

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...Continue Reading

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Citations

May 9, 2019·International Journal of Molecular Sciences·Peng ZengHu Chen
Jun 23, 2019·Cells·Takahiko Murayama, Noriko Gotoh
Aug 14, 2019·International Journal of Cancer. Journal International Du Cancer·Cristina Montero-CondeMercedes Robledo
Aug 20, 2019·The Journal of Histochemistry and Cytochemistry : Official Journal of the Histochemistry Society·Wen-Qun ZhongJi-Hong Zhao
Nov 4, 2020·Journal of Personalized Medicine·Marta Ávalos-MorenoSergio Granados-Principal
Mar 7, 2021·International Journal of Molecular Sciences·Jun NakayamaKentaro Semba
Mar 25, 2021·Cancer Management and Research·Zhitao LiBingqing Hui
Apr 1, 2021·Life Science Alliance·Lohit KheraSima Lev

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