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      Embryonic Morphogen Nodal Promotes Breast Cancer Growth and Progression

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          Abstract

          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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          Most cited references28

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          Models, mechanisms and clinical evidence for cancer dormancy.

          Patients with cancer can develop recurrent metastatic disease with latency periods that range from years even to decades. This pause can be explained by cancer dormancy, a stage in cancer progression in which residual disease is present but remains asymptomatic. Cancer dormancy is poorly understood, resulting in major shortcomings in our understanding of the full complexity of the disease. Here, I review experimental and clinical evidence that supports the existence of various mechanisms of cancer dormancy including angiogenic dormancy, cellular dormancy (G0-G1 arrest) and immunosurveillance. The advances in this field provide an emerging picture of how cancer dormancy can ensue and how it could be therapeutically targeted.
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            Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression.

            In cancer patients, dormant micrometastases are often asymptomatic and clinically undetectable, for months or years, until relapse. We have studied dormant lung metastases under angiogenesis suppression in mice. The metastases exhibited rapid growth when the inhibition of angiogenesis was removed. Tumour cell proliferation, as measured by bromodeoxyuridine incorporation and immunohistochemical staining proliferating cell nuclear antigen, was not significantly different in dormant and growing metastases. However, tumour cells of dormant metastases exhibited a more than threefold higher incidence of apoptosis. These data show that metastases remain dormant when tumour cell proliferation is balanced by an equivalent rate of cell death and suggest that angiogenesis inhibitors control metastatic growth by indirectly increasing apoptosis in tumour cells.
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              Proliferation marker Ki-67 in early breast cancer.

              Molecular markers have been extensively investigated with a view to providing early and accurate information on long-term outcome and prediction of response to treatment of early breast cancer. Proliferation is a key feature of the progression of tumors and is now widely estimated by the immunohistochemical assessment of the nuclear antigen Ki-67. The expression of Ki-67 correlates with other measurements of proliferation, including S-phase and bromodeoxyuridine uptake. High Ki-67 is a sign of poor prognosis associated with a good chance of clinical response to chemotherapy, but its independent significance is modest and does not merit measurements in most routine clinical scenarios. However, its application as a pharmacodynamic intermediate marker of the effectiveness of medical therapy holds great promise for rapid evaluation of new drugs.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2012
                7 November 2012
                : 7
                : 11
                : e48237
                Affiliations
                [1 ]Department of Anatomy & Cell Biology, University of Western Ontario, London, Ontario, Canada
                [2 ]Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
                [3 ]Department of Physiology and Pharmacology and Robarts Research Institute, London, Ontario, Canada
                University of Tampere, Finland
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: DFQ GZ LAW DAH LMP. Performed the experiments: DFQ GZ LAW GMS DZD SDF HB DMP. Analyzed the data: DFQ GZ GMS DAH LMP. Contributed reagents/materials/analysis tools: DAH LMP. Wrote the paper: DFQ LMP.

                Article
                PONE-D-12-04838
                10.1371/journal.pone.0048237
                3492336
                23144858
                7066cbc8-a94c-4747-95c3-39c108f315e6
                Copyright @ 2012

                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 credited.

                History
                : 12 February 2012
                : 26 September 2012
                Page count
                Pages: 12
                Funding
                This work was supported by the Canadian Institutes for Health Research (MOP 89714 and PLS 95381) and the Cancer Research Society to L.M.P. D.F.Q. is a recipient of a doctoral fellowship from the Canadian Breast Cancer Foundation and from the Canadian Institutes of Health Research (CIHR) Strategic Training Program in Cancer Research and Technology Transfer. L.M.P. is the recipient of the premier new investigator award from the CIHR. D.A.H. is the recipient of a new investigator award and a MacDonald Scholarship for the Canadian Heart and Stroke Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Developmental Biology
                Stem Cells
                Embryonic Stem Cells
                Cell Differentiation
                Molecular Cell Biology
                Cellular Types
                Stem Cells
                Embryonic Stem Cells
                Cell Growth
                Medicine
                Obstetrics and Gynecology
                Breast Cancer
                Oncology
                Basic Cancer Research

                Uncategorized
                Uncategorized

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