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...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2012-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3492336?pdf=render |
| _version_ | 1817984701635231744 |
|---|---|
| author | Daniela F Quail Guihua Zhang Logan A Walsh Gabrielle M Siegers Dylan Z Dieters-Castator Scott D Findlay Heather Broughton David M Putman David A Hess Lynne-Marie Postovit |
| author_facet | Daniela F Quail Guihua Zhang Logan A Walsh Gabrielle M Siegers Dylan Z Dieters-Castator Scott D Findlay Heather Broughton David M Putman David A Hess Lynne-Marie Postovit |
| author_sort | Daniela F Quail |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-13T23:48:12Z |
| format | Article |
| id | doaj.art-7915dbe6ff8a45268257ce18fb1d04f6 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-13T23:48:12Z |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-7915dbe6ff8a45268257ce18fb1d04f62022-12-22T02:24:13ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-01711e4823710.1371/journal.pone.0048237Embryonic morphogen nodal promotes breast cancer growth and progression.Daniela F QuailGuihua ZhangLogan A WalshGabrielle M SiegersDylan Z Dieters-CastatorScott D FindlayHeather BroughtonDavid M PutmanDavid A HessLynne-Marie PostovitBreast 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.http://europepmc.org/articles/PMC3492336?pdf=render |
| spellingShingle | Daniela F Quail Guihua Zhang Logan A Walsh Gabrielle M Siegers Dylan Z Dieters-Castator Scott D Findlay Heather Broughton David M Putman David A Hess Lynne-Marie Postovit Embryonic morphogen nodal promotes breast cancer growth and progression. PLoS ONE |
| 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 |
| url | http://europepmc.org/articles/PMC3492336?pdf=render |
| work_keys_str_mv | AT danielafquail embryonicmorphogennodalpromotesbreastcancergrowthandprogression AT guihuazhang embryonicmorphogennodalpromotesbreastcancergrowthandprogression AT loganawalsh embryonicmorphogennodalpromotesbreastcancergrowthandprogression AT gabriellemsiegers embryonicmorphogennodalpromotesbreastcancergrowthandprogression AT dylanzdieterscastator embryonicmorphogennodalpromotesbreastcancergrowthandprogression AT scottdfindlay embryonicmorphogennodalpromotesbreastcancergrowthandprogression AT heatherbroughton embryonicmorphogennodalpromotesbreastcancergrowthandprogression AT davidmputman embryonicmorphogennodalpromotesbreastcancergrowthandprogression AT davidahess embryonicmorphogennodalpromotesbreastcancergrowthandprogression AT lynnemariepostovit embryonicmorphogennodalpromotesbreastcancergrowthandprogression |