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Updated: Aug 15, 2025
Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
Published on: October 27, 2020
Molecular Pathways and Mechanisms of TGFβ in Cancer Therapy
Mary Helen Barcellos-Hoff1, James L Gulley2
1Department of Radiation Oncology and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California.
Abstract:
Even though the number of agents that inhibit TGFβ being tested in patients with cancer has grown substantially, clinical benefit from TGFβ inhibition has not yet been achieved. The myriad mechanisms in which TGFβ is protumorigenic may be a key obstacle to its effective deployment; cancer cells frequently employ TGFβ-regulated programs that engender plasticity, enable a permissive tumor microenvironment, and profoundly suppress immune recognition, which is the target of most current early-phase trials of TGFβ inhibitors. Here we discuss the implications of a less well-recognized aspect of TGFβ biology regulating DNA repair that mediates responses to radiation and chemotherapy. In cancers that are TGFβ signaling competent, TGFβ promotes effective DNA repair and suppresses error-prone repair, thus conferring resistance to genotoxic therapies and limiting tumor control. Cancers in which TGFβ signaling is intrinsically compromised are more responsive to standard genotoxic therapy. Recognition that TGFβ is a key moderator of both DNA repair and immunosuppression might be used to synergize combinations of genotoxic therapy and immunotherapy to benefit patients with cancer.
Insights
Transforming growth factor beta (TGFβ) inhibition shows promise in cancer, but clinical benefits remain elusive. New research reveals TGFβ
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Transforming growth factor beta (TGFβ) plays a complex role in cancer, promoting tumor growth and immune evasion.
- Current TGFβ inhibitors primarily target immunosuppression, yet clinical benefits are limited.
- TGFβ also regulates DNA repair mechanisms, influencing cancer therapy response.
Purpose of the Study:
- To explore the role of TGFβ in DNA repair and its impact on cancer treatment.
- To understand how TGFβ signaling influences resistance to genotoxic therapies.
- To identify novel therapeutic strategies combining TGFβ modulation with existing treatments.
Main Methods:
- Review of existing literature on TGFβ signaling in cancer.
- Analysis of TGFβ's role in DNA damage response pathways.
- Discussion of implications for combination cancer therapies.
Main Results:
- TGFβ signaling promotes efficient DNA repair and suppresses error-prone repair in cancer cells.
- This DNA repair function confers resistance to radiation and chemotherapy.
- Cancers with compromised TGFβ signaling are more sensitive to genotoxic therapies.
Conclusions:
- TGFβ is a critical regulator of DNA repair, impacting treatment efficacy.
- Targeting TGFβ's role in DNA repair may overcome therapy resistance.
- Combining TGFβ inhibition with genotoxic and immunotherapies could improve patient outcomes.
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