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

Abstract

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. 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 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. 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 using patient-derived xenografts (PDX). 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 2,509 patients with breast cancer. 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. .

Hsa‐miR‐139‐5p is a prognostic thyroid cancer marker involved in HNRNPF‐mediated alternative splicing

“…c ). These candidates are key proteins in the cancer‐related pathways/processes mTOR2/AKT, TGFbeta and alternative splicing, respectively, and their expression has been shown to mediate poor outcome and resistance to therapy in different cancer types including thyroid cancer …”

“…3c). These candidates are key proteins in the cancer-related pathways/processes mTOR2/AKT, TGFbeta and alternative splicing, respectively, and their expression has been shown to mediate poor outcome 24,25 and resistance to therapy 26 in different cancer types including thyroid cancer. [27][28][29] We used TargetScan version 7.0 30 to search for hsa-miR-139-5p-matched sites within the 3'UTR sequence of the candidate genes and found one 7 mer-seed matched-site for each of them (Supporting Information Fig.…”

Integrated TCGA and GEO analysis showed that SMAD7 is an independent prognostic factor for lung adenocarcinoma

“…According to a study in 2018, overexpression of ATF4 can affect the survival rate of triple-negative breast cancer patients through SMAD2. [ 30 ] Moreover, there is strong evidence that silencing SMAD2 can inhibit TGF-β function. [ 31 ] However, a previous study showed that the absence of SMAD2 could lead to reduced differentiation and increased EMT levels, leading to tumor metastasis.…”

Integrated TCGA and GEO analysis showed that SMAD7 is an independent prognostic factor for lung adenocarcinoma.

“…Similarly, SMAD2 is also involved in the regulation of many cancers. According to a study in 2018, overexpression of ATF4 can affect the survival rate of triple negative breast cancer patients through SMAD2 [31]. Moreover, there is strong evidence that silencing SMAD2 can inhibit TGFβ function [32].…”