ArticleMolecular cancer research : MCR2012
Biological responses to TGF-β in the mammary epithelium show a complex dependency on Smad3 gene dosage with important implications for tumor progression.
Article in Molecular cancer research : MCR, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 20 citations in OpenAlex.
- Analysis of the DNA-binding properties of TGF-β-activated Smad complexes unveils a possible molecular basis for cellular context-dependent signaling.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2024Article
- Interplay between tumor microenvironment and partial EMT as the driver of tumor progression.iScience · 2021Review
- Carcinogen 7,12-dimethylbenz[a]anthracene-induced mammary tumorigenesis is accelerated in Smad3 heterozygous mice compared to Smad3 wild type mice.Oncotarget · 2016Article
- In vitro differentiation of endometrial regenerative cells into smooth muscle cells: Α potential approach for the management of pelvic organ prolapse.International journal of molecular medicine · 2016Article
- Targeting metastasis.Nature reviews. Cancer · 2016Review
- Digital histologic analysis reveals morphometric patterns of age-related involution in breast epithelium and stroma.Human pathology · 2016Article
- Capillary nano-immunoassays: advancing quantitative proteomics analysis, biomarker assessment, and molecular diagnostics.Journal of translational medicine · 2015Review
- Single live cell TGF-β signalling imaging: breast cancer cell motility and migration is driven by sub-populations of cells with dynamic TGF-β-Smad3 activity.Molecular cancer · 2015Article
- Transforming growth factor-beta signaling leads to uPA/PAI-1 activation and metastasis: a study on human breast cancer tissues.Pathology oncology research : POR · 2014Article
- An integrated genomic approach identifies persistent tumor suppressive effects of transforming growth factor-β in human breast cancer.Breast cancer research : BCR · 2014Article
- Capillary isoelectric-focusing immunoassays to study dynamic oncoprotein phosphorylation and drug response to targeted therapies in non-small cell lung cancer.Molecular cancer therapeutics · 2013Article
- Overlapping substrate and inhibitor specificity of human and murine ABCG2.Drug metabolism and disposition: the biological fate of chemicals · 2013Article
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Authors and funding
11 authors at 2 institutions in 1 country.
Funding
Abstract
TGF-β plays a dual role in epithelial carcinogenesis with the potential to either suppress or promote tumor progression. We found that levels of Smad3 mRNA, a critical mediator of TGF-β signaling, are reduced by approximately 60% in human breast cancer. We therefore used conditionally immortalized mammary epithelial cells (IMEC) of differing Smad3 genotypes to quantitatively address the Smad3 requirement for different biologic responses to TGF-β. We found that a two-fold reduction in Smad3 gene dosage led to complex effects on TGF-β responses; the growth-inhibitory response was retained, the pro-apoptotic response was lost, the migratory response was reduced, and the invasion response was enhanced. Loss of the pro-apoptotic response in the Smad3(+/-) IMECs correlated with loss of Smad3 binding to the Bcl-2 locus, whereas retention of the growth-inhibitory response in Smad3 IMECs correlated with retention of Smad3 binding to the c-Myc locus. Addressing the integrated outcome of these changes in vivo, we showed that reduced Smad3 levels enhanced metastasis in two independent models of metastatic breast cancer. Our results suggest that different biologic responses to TGF-β in the mammary epithelium are differentially affected by Smad3 dosage and that a mere two-fold reduction in Smad3 is sufficient to promote metastasis.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.