Background <p>Fibrosis is a complex process that involves the excessive formation of fibrous connective tissue in triple-negative breast cancer (TNBC), often as a response to chronic inflammation and immune response. Radiation cancer therapy, paradoxically, can also lead to fibrosis in the surrounding healthy tissues. Targeting transforming growth factor beta (TGFβ), which signaling has recently been linked to fibrosis, is envisioned to improve the effectiveness of cancer therapies. Here, we hypothesized that quercetin, a diet-derived flavonoid known to alleviate pulmonary, hepatic, and kidney fibrosis, could prevent the TGFβ-mediated epithelial to mesenchymal transition (EMT) and the acquisition of a fibrotic molecular signature.</p> Methods and results <p>PCR gene arrays and RT-qPCR were used to assess fibrosis, cell senescence, and Wnt signaling transcripts expression profiles. Western blotting was used to assess protein expression in cell lysates, cytosolic and nuclear fractions. Chemotatic cell migration was assessed using the real-time xCELLigence instrument. We found that TGFβ effectively triggered an EMT and fibrotic phenotype in human MDA-MB-231 TNBC-derived cells as assessed through the increased transcript levels of <i>TWIST1</i>, <i>Fibronectin</i>, <i>COL1A1</i>, <i>COL1A2</i>, <i>COL3A1</i>, and <i>MMP9</i>, as well as protein expression of EGFR, Fibronectin, p21 and Snail. Quercetin dose-dependently prevented TGFβ-mediated phosphorylation of Smad2/3 and cell chemotaxis, as well as Snail nuclear translocation and the induction of biomarkers linking Wnt signaling to EMT-mediated fibrosis and to cell senescence molecular signature.</p> Conclusions <p>Our data suggest that quercetin can inhibit TGFβ/Smad signaling pathway and may, in part, contribute to anti-fibrotic modalities that would improve outcomes for breast cancer patients with fibrotic conditions.</p> Clinical trial number <p>Not applicable.</p>