Chaudhary Nazia, Mandal Dibita, Choudhary Bhagya Shree, Patra Sushmita, Jain Darshan, Poonia Pritam, Shaikh Shagufa, Tekalkar Siddhi, Malvankar Shivani, Shivashankar Anusha, Jog Eeshrita, Pilankar Leena, Thorat Rahul, Kailje Vaishali V, Khanna Sonal, Manna Subhakankha, Khan Bushra K, Jadhav Anjana, Sharma Kedar, Ramu Soundharya, Sahoo Sarthak, Jolly Mohit Kumar, Dalal Sorab N, Sinha Sanju, Nair Nishanth Ulhas, Ruppin Eytan, Lamballe Fabienne, Maina Flavio, Verma Nandini
Advanced Centre for Treatment, Research, and Education in Cancer, Tata Memorial Centre, Navi Mumbai, 410210, India.
Advanced Centre for Treatment, Research, and Education in Cancer, Tata Memorial Centre, Navi Mumbai, 410210, India; Homi Bhabha National Institute, Anushakti Nagar, Tata Memorial Hospital, Dr. E Borges Road, Parel, Mumbai, 400085, India.
Redox Biol. 2025 Nov;87:103864. doi: 10.1016/j.redox.2025.103864. Epub 2025 Sep 11.
Metastatic relapses in Triple-Negative Breast Cancer (TNBC) patients with residual disease pose a significant clinical challenge. In this study, we longitudinally modelled cellular state transition from dormant drug-tolerant persister (DDTP) to proliferative (PDTP) cell state across TNBC subtypes. We identified specific molecular and phenotypic alterations that characterize the DTP states in TNBC cells that are maintained upon re-gaining proliferation. We found that Basal-Like proliferative DTPs stably acquired mesenchymal traits, while luminal androgen receptor-positive TNBC DTPs undergo partial Epithelial-to-Mesenchymal Transition (EMT). TNBC DTP cells exhibit reduced expression of glutathione peroxidase-4 (GPX4), conferring susceptibility to ferroptosis inducers. Mechanistically, GPX4 downregulation promotes EMT in TNBC, supported by an inverse correlation between GPX4 and EMT marker vimentin (VIM) expression that also serves as a predictor of survival in TNBC patients undergoing chemotherapy. The genetic, pharmacological, or chemotherapy-induced suppression of GPX4 in TNBC cells leads to robust upregulation of ferroptosis suppressor protein-1 (FSP1). The clinical significance of these findings is established by a strong predictive value of FSP1/VIM signature for worst survival and incomplete pathological response in chemotherapy-treated TNBC patients. Further, targeting FSP1 re-sensitizes cells to chemotherapy, while combined inhibition of FSP1 and GPX4 is selectively lethal in proliferative DTP TNBC cells by inducing ferroptosis.
