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Embryonic Morphogen Nodal Promotes Breast Cancer Growth and Progression

Breast cancers expressing human embryonic stem cell (hESC)-associated genes are more likely to progress than well-differentiated cancers and are thus associated with poor patient prognosis. Elevated proliferation and evasion of growth control are similarly associated with disease progression, and ar...

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Autores principales: Quail, Daniela F., Zhang, Guihua, Walsh, Logan A., Siegers, Gabrielle M., Dieters-Castator, Dylan Z., Findlay, Scott D., Broughton, Heather, Putman, David M., Hess, David A., Postovit, Lynne-Marie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3492336/
https://www.ncbi.nlm.nih.gov/pubmed/23144858
http://dx.doi.org/10.1371/journal.pone.0048237
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author Quail, Daniela F.
Zhang, Guihua
Walsh, Logan A.
Siegers, Gabrielle M.
Dieters-Castator, Dylan Z.
Findlay, Scott D.
Broughton, Heather
Putman, David M.
Hess, David A.
Postovit, Lynne-Marie
author_facet Quail, Daniela F.
Zhang, Guihua
Walsh, Logan A.
Siegers, Gabrielle M.
Dieters-Castator, Dylan Z.
Findlay, Scott D.
Broughton, Heather
Putman, David M.
Hess, David A.
Postovit, Lynne-Marie
author_sort Quail, Daniela F.
collection PubMed
description Breast cancers expressing human embryonic stem cell (hESC)-associated genes are more likely to progress than well-differentiated cancers and are thus associated with poor patient prognosis. Elevated proliferation and evasion of growth control are similarly associated with disease progression, and are classical hallmarks of cancer. In the current study we demonstrate that the hESC-associated factor Nodal promotes breast cancer growth. Specifically, we show that Nodal is elevated in aggressive MDA-MB-231, MDA-MB-468 and Hs578t human breast cancer cell lines, compared to poorly aggressive MCF-7 and T47D breast cancer cell lines. Nodal knockdown in aggressive breast cancer cells via shRNA reduces tumour incidence and significantly blunts tumour growth at primary sites. In vitro, using Trypan Blue exclusion assays, Western blot analysis of phosphorylated histone H3 and cleaved caspase-9, and real time RT-PCR analysis of BAX and BCL2 gene expression, we demonstrate that Nodal promotes expansion of breast cancer cells, likely via a combinatorial mechanism involving increased proliferation and decreased apopotosis. In an experimental model of metastasis using beta-glucuronidase (GUSB)-deficient NOD/SCID/mucopolysaccharidosis type VII (MPSVII) mice, we show that although Nodal is not required for the formation of small (<100 cells) micrometastases at secondary sites, it supports an elevated proliferation:apoptosis ratio (Ki67:TUNEL) in micrometastatic lesions. Indeed, at longer time points (8 weeks), we determined that Nodal is necessary for the subsequent development of macrometastatic lesions. Our findings demonstrate that Nodal supports tumour growth at primary and secondary sites by increasing the ratio of proliferation:apoptosis in breast cancer cells. As Nodal expression is relatively limited to embryonic systems and cancer, this study establishes Nodal as a potential tumour-specific target for the treatment of breast cancer.
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spelling pubmed-34923362012-11-09 Embryonic Morphogen Nodal Promotes Breast Cancer Growth and Progression Quail, Daniela F. Zhang, Guihua Walsh, Logan A. Siegers, Gabrielle M. Dieters-Castator, Dylan Z. Findlay, Scott D. Broughton, Heather Putman, David M. Hess, David A. Postovit, Lynne-Marie PLoS One Research Article Breast cancers expressing human embryonic stem cell (hESC)-associated genes are more likely to progress than well-differentiated cancers and are thus associated with poor patient prognosis. Elevated proliferation and evasion of growth control are similarly associated with disease progression, and are classical hallmarks of cancer. In the current study we demonstrate that the hESC-associated factor Nodal promotes breast cancer growth. Specifically, we show that Nodal is elevated in aggressive MDA-MB-231, MDA-MB-468 and Hs578t human breast cancer cell lines, compared to poorly aggressive MCF-7 and T47D breast cancer cell lines. Nodal knockdown in aggressive breast cancer cells via shRNA reduces tumour incidence and significantly blunts tumour growth at primary sites. In vitro, using Trypan Blue exclusion assays, Western blot analysis of phosphorylated histone H3 and cleaved caspase-9, and real time RT-PCR analysis of BAX and BCL2 gene expression, we demonstrate that Nodal promotes expansion of breast cancer cells, likely via a combinatorial mechanism involving increased proliferation and decreased apopotosis. In an experimental model of metastasis using beta-glucuronidase (GUSB)-deficient NOD/SCID/mucopolysaccharidosis type VII (MPSVII) mice, we show that although Nodal is not required for the formation of small (<100 cells) micrometastases at secondary sites, it supports an elevated proliferation:apoptosis ratio (Ki67:TUNEL) in micrometastatic lesions. Indeed, at longer time points (8 weeks), we determined that Nodal is necessary for the subsequent development of macrometastatic lesions. Our findings demonstrate that Nodal supports tumour growth at primary and secondary sites by increasing the ratio of proliferation:apoptosis in breast cancer cells. As Nodal expression is relatively limited to embryonic systems and cancer, this study establishes Nodal as a potential tumour-specific target for the treatment of breast cancer. Public Library of Science 2012-11-07 /pmc/articles/PMC3492336/ /pubmed/23144858 http://dx.doi.org/10.1371/journal.pone.0048237 Text en © 2012 Quail et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Quail, Daniela F.
Zhang, Guihua
Walsh, Logan A.
Siegers, Gabrielle M.
Dieters-Castator, Dylan Z.
Findlay, Scott D.
Broughton, Heather
Putman, David M.
Hess, David A.
Postovit, Lynne-Marie
Embryonic Morphogen Nodal Promotes Breast Cancer Growth and Progression
title Embryonic Morphogen Nodal Promotes Breast Cancer Growth and Progression
title_full Embryonic Morphogen Nodal Promotes Breast Cancer Growth and Progression
title_fullStr Embryonic Morphogen Nodal Promotes Breast Cancer Growth and Progression
title_full_unstemmed Embryonic Morphogen Nodal Promotes Breast Cancer Growth and Progression
title_short Embryonic Morphogen Nodal Promotes Breast Cancer Growth and Progression
title_sort embryonic morphogen nodal promotes breast cancer growth and progression
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3492336/
https://www.ncbi.nlm.nih.gov/pubmed/23144858
http://dx.doi.org/10.1371/journal.pone.0048237
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