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Attenuation of TGF-β signaling suppresses premature senescence in a p21-dependent manner and promotes oncogenic Ras-mediated metastatic transformation in human mammary epithelial cells

The molecular mechanisms that drive triple-negative, basal-like breast cancer progression are elusive. Few molecular targets have been identified for the prevention or treatment of this disease. Here we developed a series of isogenic basal-like human mammary epithelial cells (HMECs) with altered tra...

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Detalles Bibliográficos
Autores principales: Lin, Shu, Yang, Junhua, Elkahloun, Abdel G., Bandyopadhyay, Abhik, Wang, Long, Cornell, John E., Yeh, I-Tien, Agyin, Joseph, Tomlinson, Gail, Sun, Lu-Zhe
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3327327/
https://www.ncbi.nlm.nih.gov/pubmed/22357622
http://dx.doi.org/10.1091/mbc.E11-10-0849
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author Lin, Shu
Yang, Junhua
Elkahloun, Abdel G.
Bandyopadhyay, Abhik
Wang, Long
Cornell, John E.
Yeh, I-Tien
Agyin, Joseph
Tomlinson, Gail
Sun, Lu-Zhe
author_facet Lin, Shu
Yang, Junhua
Elkahloun, Abdel G.
Bandyopadhyay, Abhik
Wang, Long
Cornell, John E.
Yeh, I-Tien
Agyin, Joseph
Tomlinson, Gail
Sun, Lu-Zhe
author_sort Lin, Shu
collection PubMed
description The molecular mechanisms that drive triple-negative, basal-like breast cancer progression are elusive. Few molecular targets have been identified for the prevention or treatment of this disease. Here we developed a series of isogenic basal-like human mammary epithelial cells (HMECs) with altered transforming growth factor-β (TGF-β) sensitivity and different malignancy, resembling a full spectrum of basal-like breast carcinogenesis, and determined the molecular mechanisms that contribute to oncogene-induced transformation of basal-like HMECs when TGF-β signaling is attenuated. We found that expression of a dominant-negative type II receptor (DNRII) of TGF-β abrogated autocrine TGF-β signaling in telomerase-immortalized HMECs and suppressed H-Ras-V12–induced senescence-like growth arrest (SLGA). Furthermore, coexpression of DNRII and H-Ras-V12 rendered HMECs highly tumorigenic and metastatic in vivo in comparison with H-Ras-V12–transformed HMECs that spontaneously escaped H-Ras-V12–induced SLGA. Microarray analysis revealed that p21 was the major player mediating Ras-induced SLGA, and attenuated or loss of p21 expression contributed to the escape from SLGA when autocrine TGF-β signaling was blocked in HMECs. Furthermore, knockdown of p21 also suppressed H-Ras-V12–induced SLGA. Our results identify that autocrine TGF-β signaling is an integral part of the cellular anti-transformation network by suppressing the expression of a host of genes, including p21-regulated genes, that mediate oncogene-induced transformation in basal-like breast cancer.
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spelling pubmed-33273272012-06-30 Attenuation of TGF-β signaling suppresses premature senescence in a p21-dependent manner and promotes oncogenic Ras-mediated metastatic transformation in human mammary epithelial cells Lin, Shu Yang, Junhua Elkahloun, Abdel G. Bandyopadhyay, Abhik Wang, Long Cornell, John E. Yeh, I-Tien Agyin, Joseph Tomlinson, Gail Sun, Lu-Zhe Mol Biol Cell Articles The molecular mechanisms that drive triple-negative, basal-like breast cancer progression are elusive. Few molecular targets have been identified for the prevention or treatment of this disease. Here we developed a series of isogenic basal-like human mammary epithelial cells (HMECs) with altered transforming growth factor-β (TGF-β) sensitivity and different malignancy, resembling a full spectrum of basal-like breast carcinogenesis, and determined the molecular mechanisms that contribute to oncogene-induced transformation of basal-like HMECs when TGF-β signaling is attenuated. We found that expression of a dominant-negative type II receptor (DNRII) of TGF-β abrogated autocrine TGF-β signaling in telomerase-immortalized HMECs and suppressed H-Ras-V12–induced senescence-like growth arrest (SLGA). Furthermore, coexpression of DNRII and H-Ras-V12 rendered HMECs highly tumorigenic and metastatic in vivo in comparison with H-Ras-V12–transformed HMECs that spontaneously escaped H-Ras-V12–induced SLGA. Microarray analysis revealed that p21 was the major player mediating Ras-induced SLGA, and attenuated or loss of p21 expression contributed to the escape from SLGA when autocrine TGF-β signaling was blocked in HMECs. Furthermore, knockdown of p21 also suppressed H-Ras-V12–induced SLGA. Our results identify that autocrine TGF-β signaling is an integral part of the cellular anti-transformation network by suppressing the expression of a host of genes, including p21-regulated genes, that mediate oncogene-induced transformation in basal-like breast cancer. The American Society for Cell Biology 2012-04-15 /pmc/articles/PMC3327327/ /pubmed/22357622 http://dx.doi.org/10.1091/mbc.E11-10-0849 Text en © 2012 Lin et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society of Cell Biology.
spellingShingle Articles
Lin, Shu
Yang, Junhua
Elkahloun, Abdel G.
Bandyopadhyay, Abhik
Wang, Long
Cornell, John E.
Yeh, I-Tien
Agyin, Joseph
Tomlinson, Gail
Sun, Lu-Zhe
Attenuation of TGF-β signaling suppresses premature senescence in a p21-dependent manner and promotes oncogenic Ras-mediated metastatic transformation in human mammary epithelial cells
title Attenuation of TGF-β signaling suppresses premature senescence in a p21-dependent manner and promotes oncogenic Ras-mediated metastatic transformation in human mammary epithelial cells
title_full Attenuation of TGF-β signaling suppresses premature senescence in a p21-dependent manner and promotes oncogenic Ras-mediated metastatic transformation in human mammary epithelial cells
title_fullStr Attenuation of TGF-β signaling suppresses premature senescence in a p21-dependent manner and promotes oncogenic Ras-mediated metastatic transformation in human mammary epithelial cells
title_full_unstemmed Attenuation of TGF-β signaling suppresses premature senescence in a p21-dependent manner and promotes oncogenic Ras-mediated metastatic transformation in human mammary epithelial cells
title_short Attenuation of TGF-β signaling suppresses premature senescence in a p21-dependent manner and promotes oncogenic Ras-mediated metastatic transformation in human mammary epithelial cells
title_sort attenuation of tgf-β signaling suppresses premature senescence in a p21-dependent manner and promotes oncogenic ras-mediated metastatic transformation in human mammary epithelial cells
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3327327/
https://www.ncbi.nlm.nih.gov/pubmed/22357622
http://dx.doi.org/10.1091/mbc.E11-10-0849
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