Novel Insights into TNBC Cell Death Modulation by Trypanosoma cruzi Parasite Extracts

The protozoan parasite Trypanosoma cruzi (T. cruzi) causes American trypanosomiasis or Chagas disease. While chronic T. cruzi infection is associated with the development of gastrointestinal and esophageal cancers, T. cruzi proteins, including cell surface antigens, exhibit anti-tumor effects. This novel study focuses on triple-negative breast cancer (TNBC), which lacks estrogen and progesterone receptors as well as the human epidermal growth factor receptor-2. Compared to other invasive breast cancer types, TNBC tumors are frequently resistant to standard of care and most targeted treatments. Thus, there is an urgent need for nonconventional therapeutics to antagonize TNBC progression. In this study, we investigated how T. cruzi extracts affect the viability of phenotypically distinct TNBC cell models. We isolated whole parasite, membrane, and cytosolic fractions of T. cruzi trypomastigotes and treated basal-like MDA-468 and mesenchymal-like BT-549 TNBC cells with these extracts. We then performed cell proliferation, autophagy, apoptosis and DNA damage assays to evaluate T. cruzi-induced cell death. Our data show that both T. cruzi membrane and cytosolic extracts inhibit the viability of mesenchymal-like and basal-like TNBC cells. However, these parasite extracts significantly induced PARP1 cleavage in MDA-468 cells and upregulated the expression of the autophagic marker, LC3B-II in BT-549 cells. Bulk RNA sequencing of control and parasite extract-treated TNBC cells revealed significant alterations in the transcriptome. These parasite extracts altered the expression of genes involved in several pathways including cellular stress and proinflammatory signaling. Collectively, our findings demonstrate that T. cruzi extracts reduce TNBC cell viability through the activation of multiple cell death pathways and specifically via DNA damage in epithelial TNBC cells and autophagy in mesenchymal-like TNBC cells. These data highlight the potential of T. cruzi-derived components as nonconventional therapeutic agents for the treatment of the hard-to-treat triple-negative breast cancer. This project was supported, in part, by NIH/NIGMS SC1GM139814, NIH/NIAID T32AI007281, NIH U54MD007586 and an Education Gift from Dr. Bernard Crowe. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.