Abstract 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, protein components of T. cruzi parasite extracts, as well as cell surface antigens, do exhibit anti-tumor effects. This novel study focuses on triple-negative breast cancer (TNBC), that lacks estrogen and progesterone receptors as well as the human epidermal growth factor receptor-2. Compared to other invasive breast cancer types, TNBC patients are often resistant to conventional methods of treatment. Thus, there is a need for nonconventional therapeutics to antagonize tumor progression. In this study, we investigated how T. cruzi parasite extracts affect the viability of TNBC cell models. We isolated membrane and cytosolic fractions of T. cruzi trypomastigotes and treated basal-like MDA-468 and mesenchymal BT-549 triple-negative breast cancer cell lines with the whole parasite, cytosolic and membrane fractions. We then performed cell proliferation, autophagy, apoptosis and DNA damage assays to evaluate T. cruzi-induced cell death. These parasite extracts significantly induced PARP1 cleavage in MDA-468 cells and upregulated the expression of autophagic marker, LC3B-II in BT-549 cells. To identify potential molecular mechanisms, we isolated RNA for RNA sequencing to evaluate alterations in the transcriptome. Our data show that both T. cruzi membrane and cytosolic extracts inhibit the viability of mesenchymal-like and basal-like TNBC cells. These parasite extracts significantly affected several pathways including cellular stress, and proinflammatory signaling pathways. Collectively, our findings demonstrate that T. cruzi membrane and cytosolic extracts suppress TNBC cell viability through the activation of multiple cell death pathways. These results highlight the potential of T. cruzi-derived components as nonconventional therapeutic agents for the treatment of 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. Citation Format: D. D. Ball, K. J. Rayford, A. Cooley, S. Briseno-Gonzalez, P. Nde, A. Sakwe. Trypanosoma cruzi Extracts Modulate Diverse Death Signaling Pathways in Triple Negative Breast Cancer abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-13-14.
Ball et al. (Tue,) studied this question.