Triple-negative breast cancer is a type in which TNBC, estrogen and progesterone, and the HER2 protein are all absent, and it is notorious as the most aggressive among breast cancers. Chemotherapy works well at first, but some cancer cells survive, lie dormant, and then regrow, causing recurrence in 20%–30% of patients.
French scientists have clarified in detail how such chemotherapy-tolerant "persister cells" arise and how they regrow tumors. As there is still no clear method to find and eliminate cells once they go dormant, the study was evaluated as opening a path to treat malignant breast cancer.
A joint team from the National Center for Scientific Research (CNRS), Institut Curie, and Sorbonne University announced on the 6th (local time) in the international journal Cancer Research that persister cells in triple-negative breast cancer patients show similar gene activity patterns (a common transcriptional program) even when the treatments patients received differ.
In particular, it was confirmed that persister cells withstand treatment by changing their own gene expression patterns without genetic mutations. The researchers described this not as a breakdown of DNA but as "non-genetic adaptation," in which cancer cells temporarily switch their mode of operation to overcome a crisis.
The study used persister cells obtained by implanting tumor tissues from eight patients secured at Institut Curie into mice. The researchers tracked changes in cancer cells before and after treatment to examine how persister cells arise and persist, and how they revert to the initial state to prepare for recurrence.
As a result, persister cells flexibly adjusted gene expression during treatment, transformed into a completely different state to endure, and then returned to their original state and proliferated once the danger passed. It is like a bear and other animals going into hibernation to reduce metabolic activity when temperatures drop and resuming activity when spring arrives.
Regardless of various treatment conditions, persister cells showed increased basal keratin proteins seen in keratinocytes and activation of stress and inflammatory response pathways. These features were observed not only in triple-negative breast cancer but also during treatment of HER2-positive breast cancer and lung cancer. This means it is not a problem unique to a specific cancer but a survival strategy shared by several cancers.
The researchers confirmed that transcription factors such as AP-1, NF-κB, and IRF/STAT (regulators that turn genes on and off) sit at the center of the gene network controlling the state of persister cells. Mediated by stress and inflammatory signals, they played the role of a "conductor," maintaining the persister cell state and ultimately coordinating gene activity that enables recurrence.
The researchers expected that these results would lead to the development of biomarkers that predict recurrence risk and to combination therapy strategies that block entry into the persister cell stage. If the goal of existing cancer treatment is to eliminate as many cancer cells as possible, preventing cancer cells from entering the persister cell state could become a new challenge going forward.
References
Cancer Research (2025), DOI: https://doi.org/10.1158/0008-5472.CAN-25-0995