Document Type
Presentation
Abstract
Triple negative breast cancer (TNBC) cells do not express estrogen and progesterone receptors, and do not produce increased amounts of the human EGF receptor 2 (HER2) protein. TNBC is aggressive, prone to metastasis, and a notably challenging type of cancer to treat due to the lack of tumor-specific targeted therapy. As a result, chemotherapy is used as a systemic treatment for TNBC, and chemotherapeutic anthracyclines, including doxorubicin (Dox), are used as adjuvants to surgical excision of the tumor in the treatment of TNBC. Albeit an effective anticancer agent, Dox is notoriously known to cause cardiovascular complications in treated patients. We have previously shown that Dox increases the activity of the canonical TGF-beta/SMAD3 pathway in cardiac cell types, and inhibition of this pathway alleviates cardiovascular complications induced by Dox. The canonical TGF-beta pathway may initially act as a tumor suppressor but promotes cancer progression and metastases at the later stages of cancer. Given the critical role of the TGF-beta pathway in cancer progression, we set out to test the hypothesis that Dox will enhance the activity of the TGF-beta pathway in cultured TNBC cells. Phosphorylation of SMAD3, one of the transcription factors in the pathway, was increased in the Dox-treated 4T1 TNBC cancer cells, indicating the increased activity of the pathway. This concept was further supported in experiments with the CAGA12-Luc luciferase reporter plasmid that also showed increased activation of the pathway upon exposure of the Dox-treated 4T1 cells to transforming growth factor-beta1 (TGF-beta1). Furthermore, transcriptomic analysis demonstrated increased activity of SMAD2, SMAD3, and SMAD4 upstream regulators upon Dox treatment of the TNBC cells. Notably, SB431542 (SB), a selective inhibitor of the canonical TGF-beta pathway, significantly reduced activation of the pathway in the Dox-treated 4T1 cells, as shown in both SMAD3 phosphorylation and RNA-sequencing experiments. Thus, these results suggest that 1) Dox enhanced activity of the TGF-beta canonical pathway in cultured TNBC cells; and 2) targeted inhibition of the pathway may become a novel approach to prevent its deleterious effects during Dox therapy.
Publication Date
2026
