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

Adrián González-González, Esperanza Muñoz-Muela, Juan A. Marchal, Francisca E. Cara, Maria P. Molina, Marina Cruz-Lozano, Gema Jiménez, Akanksha Verma, Alberto Ramírez, Wei Qian, Wen Chen, Anthony J. Kozielski, Olivier Elemento, María D. Martín-Salvago, Rafael J. Luque, Carmen Rosa-Garrido, David Landeira, María Quintana-Romero, Roberto R. Rosato, Maria A. García & 9 others Cesar L. Ramirez-Tortosa, Hanna Kim, Cristian Rodriguez-Aguayo, Gabriel Lopez, Anil K Sood, Jose A. Lorente, Pedro Sánchez-Rovira, Jenny C. Chang, Sergio Granados-Principal

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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.

LanguageEnglish (US)
Pages5697-5709
Number of pages13
JournalClinical cancer research : an official journal of the American Association for Cancer Research
Volume24
Issue number22
DOIs
StatePublished - Nov 15 2018

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Activating Transcription Factor 4
Triple Negative Breast Neoplasms
Survival
Breast Neoplasms
Heterografts
TOR complex 2
Neoplasm Metastasis
Genes
Neoplasms
Epithelial-Mesenchymal Transition
Kaplan-Meier Estimate

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Activating Transcription Factor 4 Modulates TGFβ-Induced Aggressiveness in Triple-Negative Breast Cancer via SMAD2/3/4 and mTORC2 Signaling. / González-González, Adrián; Muñoz-Muela, Esperanza; Marchal, Juan A.; Cara, Francisca E.; Molina, Maria P.; Cruz-Lozano, Marina; Jiménez, Gema; Verma, Akanksha; Ramírez, Alberto; Qian, Wei; Chen, Wen; Kozielski, Anthony J.; Elemento, Olivier; Martín-Salvago, María D.; Luque, Rafael J.; Rosa-Garrido, Carmen; Landeira, David; Quintana-Romero, María; Rosato, Roberto R.; García, Maria A.; Ramirez-Tortosa, Cesar L.; Kim, Hanna; Rodriguez-Aguayo, Cristian; Lopez, Gabriel; Sood, Anil K; Lorente, Jose A.; Sánchez-Rovira, Pedro; Chang, Jenny C.; Granados-Principal, Sergio.

In: Clinical cancer research : an official journal of the American Association for Cancer Research, Vol. 24, No. 22, 15.11.2018, p. 5697-5709.

Research output: Contribution to journalArticle

González-González, A, Muñoz-Muela, E, Marchal, JA, Cara, FE, Molina, MP, Cruz-Lozano, M, Jiménez, G, Verma, A, Ramírez, A, Qian, W, Chen, W, Kozielski, AJ, Elemento, O, Martín-Salvago, MD, Luque, RJ, Rosa-Garrido, C, Landeira, D, Quintana-Romero, M, Rosato, RR, García, MA, Ramirez-Tortosa, CL, Kim, H, Rodriguez-Aguayo, C, Lopez, G, Sood, AK, Lorente, JA, Sánchez-Rovira, P, Chang, JC & Granados-Principal, S 2018, '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, vol. 24, no. 22, pp. 5697-5709. https://doi.org/10.1158/1078-0432.CCR-17-3125
González-González, Adrián ; Muñoz-Muela, Esperanza ; Marchal, Juan A. ; Cara, Francisca E. ; Molina, Maria P. ; Cruz-Lozano, Marina ; Jiménez, Gema ; Verma, Akanksha ; Ramírez, Alberto ; Qian, Wei ; Chen, Wen ; Kozielski, Anthony J. ; Elemento, Olivier ; Martín-Salvago, María D. ; Luque, Rafael J. ; Rosa-Garrido, Carmen ; Landeira, David ; Quintana-Romero, María ; Rosato, Roberto R. ; García, Maria A. ; Ramirez-Tortosa, Cesar L. ; Kim, Hanna ; Rodriguez-Aguayo, Cristian ; Lopez, Gabriel ; Sood, Anil K ; Lorente, Jose A. ; Sánchez-Rovira, Pedro ; Chang, Jenny C. ; Granados-Principal, Sergio. / Activating Transcription Factor 4 Modulates TGFβ-Induced Aggressiveness in Triple-Negative Breast Cancer via SMAD2/3/4 and mTORC2 Signaling. In: Clinical cancer research : an official journal of the American Association for Cancer Research. 2018 ; Vol. 24, No. 22. pp. 5697-5709.
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title = "Activating Transcription Factor 4 Modulates TGFβ-Induced Aggressiveness in Triple-Negative Breast Cancer via SMAD2/3/4 and mTORC2 Signaling",
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.",
author = "Adri{\'a}n Gonz{\'a}lez-Gonz{\'a}lez and Esperanza Mu{\~n}oz-Muela and Marchal, {Juan A.} and Cara, {Francisca E.} and Molina, {Maria P.} and Marina Cruz-Lozano and Gema Jim{\'e}nez and Akanksha Verma and Alberto Ram{\'i}rez and Wei Qian and Wen Chen and Kozielski, {Anthony J.} and Olivier Elemento and Mart{\'i}n-Salvago, {Mar{\'i}a D.} and Luque, {Rafael J.} and Carmen Rosa-Garrido and David Landeira and Mar{\'i}a Quintana-Romero and Rosato, {Roberto R.} and Garc{\'i}a, {Maria A.} and Ramirez-Tortosa, {Cesar L.} and Hanna Kim and Cristian Rodriguez-Aguayo and Gabriel Lopez and Sood, {Anil K} and Lorente, {Jose A.} and Pedro S{\'a}nchez-Rovira and Chang, {Jenny C.} and Sergio Granados-Principal",
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T1 - Activating Transcription Factor 4 Modulates TGFβ-Induced Aggressiveness in Triple-Negative Breast Cancer via SMAD2/3/4 and mTORC2 Signaling

AU - González-González, Adrián

AU - Muñoz-Muela, Esperanza

AU - Marchal, Juan A.

AU - Cara, Francisca E.

AU - Molina, Maria P.

AU - Cruz-Lozano, Marina

AU - Jiménez, Gema

AU - Verma, Akanksha

AU - Ramírez, Alberto

AU - Qian, Wei

AU - Chen, Wen

AU - Kozielski, Anthony J.

AU - Elemento, Olivier

AU - Martín-Salvago, María D.

AU - Luque, Rafael J.

AU - Rosa-Garrido, Carmen

AU - Landeira, David

AU - Quintana-Romero, María

AU - Rosato, Roberto R.

AU - García, Maria A.

AU - Ramirez-Tortosa, Cesar L.

AU - Kim, Hanna

AU - Rodriguez-Aguayo, Cristian

AU - Lopez, Gabriel

AU - Sood, Anil K

AU - Lorente, Jose A.

AU - Sánchez-Rovira, Pedro

AU - Chang, Jenny C.

AU - Granados-Principal, Sergio

PY - 2018/11/15

Y1 - 2018/11/15

N2 - 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.

AB - 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.

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