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The Outcome of TGFβ Antagonism in Metastatic Breast Cancer Models In Vivo Reflects a Complex Balance between Tumor-Suppressive and Proprogression Activities of TGFβ
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Abstract
Purpose: TGFβs are overexpressed in many advanced cancers and promote cancer progression through mechanisms that include suppression of immunosurveillance. Multiple strategies to antagonize the TGFβ pathway are in early-phase oncology trials. However, TGFβs also have tumor-suppressive activities early in tumorigenesis, and the extent to which these might be retained in advanced disease has not been fully explored. Experimental Design: A panel of 12 immunocompetent mouse allograft models of metastatic breast cancer was tested for the effect of neutralizing anti-TGFβ antibodies on lung metastatic burden. Extensive correlative biology analyses were performed to assess potential predictive biomarkers and probe underlying mechanisms. Results: Heterogeneous responses to anti-TGFβ treatment were observed, with 5 of 12 models (42%) showing suppression of metastasis, 4 of 12 (33%) showing no response, and 3 of 12 (25%) showing an undesirable stimulation (up to 9-fold) of metastasis. Inhibition of metastasis was immune-dependent, whereas stimulation of metastasis was immune-independent and targeted the tumor cell compartment, potentially affecting the cancer stem cell. Thus, the integrated outcome of TGFβ antagonism depends on a complex balance between enhancing effective antitumor immunity and disrupting persistent tumor-suppressive effects of TGFβ on the tumor cell. Applying transcriptomic signatures derived from treatment-naïve mouse primary tumors to human breast cancer datasets suggested that patients with breast cancer with high-grade, estrogen receptor–negative disease are most likely to benefit from anti-TGFβ therapy. Conclusions: Contrary to dogma, tumor-suppressive responses to TGFβ are retained in some advanced metastatic tumors. Safe deployment of TGFβ antagonists in the clinic will require good predictive biomarkers.
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“TGF-β2 was reported to contribute to metastatic tumor dormancy333–335”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [333]
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Metadata
- Authors
- Yang, Y., Yang, H. H., Tang, B., Wu, A. M. L., Flanders, K. C., Moshkovich, N., Weinberg, D. S., Welsh, M. A., Weng, J., Ochoa, H. J., Hu, T. Y., Herrmann, M. A., Chen, J., Edmondson, E. F., Simpson, R. M., Liu, F., Liu, H., Lee, M. P., & Wakefield, L. M.
- Affiliations
- 1Lab of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
- National Cancer Institute (US)
- Frederick National Laboratory for Cancer Research (US)
- Rutgers, The State University of New Jersey (US)
- Corresponding author
- Wakefield, Lalage M.
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2020-02-01
- Volume
- 26
- Issue
- 3
- Pages
- 643-656
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC8182485
- OpenAlex
- W2977670851
- Cited by
- 29
- References
- 53
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 2 · 2023: 3 · 2022: 4 · 2021: 7 · 2020: 4
- FWCI
- 1.24
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (ZIA BC 010881)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- metastatic breast cancer, anti-TGF-beta antibody, tumor suppression, tumor progression, lung metastasis, antitumor immunity, cancer stem cells, predictive biomarkers, estrogen receptor-negative breast cancer
- MeSH terms
- Antineoplastic Agents, Immunological, Animals, Breast Neoplasms, Disease Models, Animal, Female, Humans, Lung Neoplasms, Mice, Inbred BALB C, Mice, Inbred C57BL, Neoplastic Stem Cells, Signal Transduction, Gene Expression Regulation, Neoplastic, Genes, Tumor Suppressor, Transforming Growth Factor beta, Treatment Outcome, Cell Line, Tumor, Mice
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