E2A Modulates Stemness, Metastasis, and Therapeutic Resistance of Breast Cancer

Cancer stem cells (CSC) are considered responsible for tumor initiation, therapeutic resistance, and metastasis. A comprehensive knowledge of the mechanisms governing the acquisition and maintenance of cancer stemness is crucial for the development of new therapeutic approaches in oncology. E2A basi...

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Veröffentlicht in:Cancer research (Chicago, Ill.) Ill.), 2021-09, Vol.81 (17), p.4529-4544
Hauptverfasser: López-Menéndez, Celia, Vázquez-Naharro, Alberto, Santos, Vanesa, Dubus, Pierre, Santamaría, Patricia G, Martínez-Ramírez, Ángel, Portillo, Francisco, Moreno-Bueno, Gema, Faraldo, Marisa M, Cano, Amparo
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container_end_page 4544
container_issue 17
container_start_page 4529
container_title Cancer research (Chicago, Ill.)
container_volume 81
creator López-Menéndez, Celia
Vázquez-Naharro, Alberto
Santos, Vanesa
Dubus, Pierre
Santamaría, Patricia G
Martínez-Ramírez, Ángel
Portillo, Francisco
Moreno-Bueno, Gema
Faraldo, Marisa M
Cano, Amparo
description Cancer stem cells (CSC) are considered responsible for tumor initiation, therapeutic resistance, and metastasis. A comprehensive knowledge of the mechanisms governing the acquisition and maintenance of cancer stemness is crucial for the development of new therapeutic approaches in oncology. E2A basic helix-loop-helix (bHLH) transcription factors are associated with epithelial-mesenchymal transition (EMT) and tumor progression, but knowledge of their functional contributions to cancer biology is still limited. Using a combination of and analyses in a novel PyMT-E2A conditional knockout mouse model and derived primary tumor cell lines, we report here an essential role of E2A in stemness, metastasis, and therapeutic resistance in breast cancer. Targeted deletion of E2A in the mammary gland impaired tumor-initiating ability and dedifferentiation potential and severely compromised metastatic competence of PyMT-driven mammary tumors. Mechanistic studies in PyMT-derived cell lines indicated that E2A actions are mediated by the upregulation of Snai1 transcription. Importantly, high E2A and SNAIL1 expression occurred in aggressive human basal-like breast carcinomas, highlighting the relevance of the E2A-Snail1 axis in metastatic breast cancer. In addition, E2A factors contributed to the maintenance of genomic integrity and resistance to PARP inhibitors in PyMT and human triple-negative breast cancer cells. Collectively, these results support the potential for E2A transcription factors as novel targets worthy of translational consideration in breast cancer. SIGNIFICANCE: These findings identify key functions of E2A factors in breast cancer cell stemness, metastasis, and drug resistance, supporting a therapeutic vulnerability to targeting E2A proteins in breast cancer.
doi_str_mv 10.1158/0008-5472.CAN-20-2685
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Importantly, high E2A and SNAIL1 expression occurred in aggressive human basal-like breast carcinomas, highlighting the relevance of the E2A-Snail1 axis in metastatic breast cancer. In addition, E2A factors contributed to the maintenance of genomic integrity and resistance to PARP inhibitors in PyMT and human triple-negative breast cancer cells. Collectively, these results support the potential for E2A transcription factors as novel targets worthy of translational consideration in breast cancer. 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Importantly, high E2A and SNAIL1 expression occurred in aggressive human basal-like breast carcinomas, highlighting the relevance of the E2A-Snail1 axis in metastatic breast cancer. In addition, E2A factors contributed to the maintenance of genomic integrity and resistance to PARP inhibitors in PyMT and human triple-negative breast cancer cells. Collectively, these results support the potential for E2A transcription factors as novel targets worthy of translational consideration in breast cancer. 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subjects Adult
Aged
Aged, 80 and over
Animals
Basic Helix-Loop-Helix Transcription Factors - metabolism
Breast Neoplasms - genetics
Breast Neoplasms - metabolism
Cancer
Carcinogenesis
Cell Differentiation
Cell Line, Tumor
Cell Transformation, Neoplastic
Computer Simulation
Drug Resistance, Neoplasm
Epithelial-Mesenchymal Transition
Female
Gene Deletion
Genome
Genotype
Humans
Life Sciences
Mammary Neoplasms, Animal
Mice
Mice, Inbred C57BL
Middle Aged
Neoplasm Metastasis
Neoplastic Stem Cells
Phthalazines - pharmacology
Piperazines - pharmacology
Snail Family Transcription Factors - metabolism
Transgenes
Triple Negative Breast Neoplasms - genetics
Triple Negative Breast Neoplasms - metabolism
title E2A Modulates Stemness, Metastasis, and Therapeutic Resistance of Breast Cancer
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