From: insideprecisionmedicine.com`
New research sheds light on the molecular mechanisms that allow breast cancer cells to survive treatment and reawaken later, often in a more aggressive and chemoresistant form.
Published in Science Signaling, the study identifies a key set of transcription factors—OVOL1 and OVOL2—that promote dormancy in aggressive breast cancer cells. These factors induce a shift in cell identity and initiate a unique survival program that allows cells to lie dormant, escape detection, and eventually re-enter the cell cycle.
“Relapses of dormant metastases might occur in patients as long as 15 to 20 years after surgical removal of the primary tumor,” the authors wrote. Dormancy refers to a prolonged period of cell cycle arrest during which cancer cells stop proliferating but remain viable. Disseminated tumor cells (DTCs) that seed distant organs can persist in this silent state for years. While dormant, they resist chemotherapy and other treatments that target dividing cells. Understanding the molecular cues that govern entry into and exit from dormancy could offer powerful new strategies to prevent cancer relapse.
OVOLs: Gatekeepers of dormancy
To simulate the transition to dormancy, the researchers overexpressed the transcription factors OVOL1 and OVOL2 in highly aggressive, mesenchymal-like breast cancer cells. These proteins are known for their roles in promoting epithelial lineage differentiation, such as during hair follicle and mammary gland development.
Overexpression of OVOL1 and OVOL2 halted cell proliferation, reduced migration, and induced a more epithelial-like morphology. In essence, the transcription factors reversed epithelial-to-mesenchymal transition (EMT), a hallmark of metastatic behavior, and promoted a mesenchymal-to-epithelial transition (MET) that coincided with dormancy.
“Our results raise the possibility that epithelialization and acquisition of the dormant state are controlled by epithelial transcription factors, including OVOL1, which is hormone dependent, regulates redox homeostasis, and permits accumulation of DNA damage,” the authors wrote.
Notably, the OVOLs also activated a poorly characterized gene called C1ORF116, which the team identified as a critical mediator of dormancy.
A double-edged sword: Autophagy and oxidative stress
C1ORF116 emerged as a key player in selective autophagy—the process by which cells recycle specific components to survive under stress. Acting like an autophagy receptor, C1ORF116 targets antioxidant proteins such as thioredoxin and glutamate-cysteine ligase for degradation. This unusual activity leads to increased levels of reactive oxygen species (ROS) and suppression of the antioxidant response.
While this environment of oxidative stress contributes to growth arrest and helps maintain dormancy, it also sets the stage for eventual relapse.
Over time, elevated ROS levels result in DNA damage and genomic instability, which may allow dormant cells to escape growth arrest and become more aggressive.
“We propose that unchecked DNA damage that occurs during mass dormancy because of elevated ROS, DNA oxidation, and double-strand DNA breaks might increase the genetic heterogeneity of DTCs,” the authors wrote. The authors thereby suggest that the very mechanisms that promote dormancy also plant the seeds of relapse.
C1ORF116: A prognostic marker?
Importantly, the researchers found that C1ORF116 is more highly expressed in breast tumors than in normal tissue and that its expression correlates with poorer outcomes in patients. The gene’s role as an autophagy receptor and regulator of redox homeostasis could make it a valuable biomarker for predicting relapse risk and monitoring dormant tumor cell populations.
Moreover, the study connects OVOL1/2 signaling to disruptions in DNA repair pathways. Dormant cells exhibited signs of DNA oxidation, double-strand breaks, and altered activity of key kinases like p38-MAPK and ATM, suggesting that OVOL-driven dormancy is not a passive process but one involving active remodeling of cellular stress responses.
Implications for therapy and monitoring
The findings offer important insights into how breast cancer cells survive long-term therapy and lay the groundwork for new approaches to target dormant cells before they awaken.
By identifying the molecular programs that sustain dormancy, the team aims to design strategies that either maintain this state indefinitely or eliminate dormant cells altogether.
One provocative implication of the study is that hormonal signals may influence dormancy. Since OVOL1 and OVOL2 are regulated by steroid hormones and growth factors, shifts in hormone levels, such as those associated with aging or menopause, could potentially trigger dormant cells to reawaken.
This raises the possibility that hormone therapies or other interventions could be used not only to treat active tumors but to maintain dormancy or prevent escape.
Barbara Jacoby is an award winning blogger that has contributed her writings to multiple online publications that have touched readers worldwide.