Breast cancer remains one of the most challenging diseases in oncology, in part due to its capacity for late recurrence. Despite advances in therapy that have turned many diagnoses into manageable or even curable conditions, some breast cancer cells have the insidious ability to lie dormant for years or even decades before re-emerging with renewed vigor. This baffling phenomenon of cancer cell dormancy has long puzzled researchers, and its underlying mechanisms remained poorly understood—until a recent breakthrough study from the Weizmann Institute of Science, led by the renowned Prof. Yosef Yarden, provided critical new insights into how breast cancer cells sleep and subsequently awaken as more aggressive malignancies.
Breast tissue is dynamic, undergoing profound transformations throughout a woman’s life. From embryonic stages through puberty and hormonal changes associated with pregnancy and lactation, breast cells transition between mesenchymal and epithelial states. The mesenchymal phase marks an early developmental stage characterized by round, highly motile, and rapidly dividing cells. In contrast, the epithelial phase represents a mature, cuboidal cell morphology with limited motility and slower proliferation. Under normal physiological conditions, cells shuttle between these states through tightly regulated mechanisms that ensure tissue homeostasis.
However, the hijacking of this natural plasticity is central to breast cancer initiation and progression. Malignancy often begins when epithelial breast cells regress, recapitulating the mesenchymal phenotype that confers enhanced migratory capacity and uncontrolled proliferation—hallmarks of cancer. Intriguingly, this same cellular plasticity facilitates the opposite transition during metastasis, allowing disseminated cancer cells to revert to a dormant epithelial-like state characterized by cell cycle arrest and metabolic quiescence. This dormant state is thought to shield cancer cells from therapies and immune surveillance, enabling them to persist quietly in distant organs for prolonged intervals.
One of the pivotal discoveries from Yarden’s laboratory focuses on the role of OVOL proteins, transcription factors instrumental in regulating the epithelial-mesenchymal axis during normal breast development. Leveraging a sophisticated three-dimensional tumor microenvironment model, combined with genetic engineering techniques, the researchers induced overexpression of OVOL1 and OVOL2 proteins in highly aggressive triple-negative breast cancer (TNBC) cells—cancers notorious for their poor prognosis and limited treatment options. Remarkably, heightened OVOL expression arrested the cellular lifecycle of these TNBC cells, enforcing dormancy and dramatically suppressing tumor growth both in vitro and in vivo in xenografted female mice.
Despite the intuitive appeal of halting tumor growth, OVOL1’s involvement in dormancy revealed a dark paradox. The team found that breast tissues of cancer patients frequently harbor elevated OVOL1 levels, suggesting a dual role for this protein. In the short term, OVOL1 suppresses proliferation, acting as a brake on malignancy. Over the long term, however, elevated OVOL1 facilitates cancer cell survival by enabling the dormancy program, allowing cells to evade detection and persist in the body. When environmental or hormonal changes trigger a decline in OVOL1 expression, dormant cells abruptly resume proliferation, often displaying heightened aggressiveness.
Further interrogation of the molecular controls governing OVOL expression uncovered critical regulatory influences of growth factors and steroid hormones. Specifically, the study revealed that certain growth factors promote OVOL1 synthesis, reinforcing dormancy, whereas estrogen—through its receptor pathway—suppresses OVOL1 expression. This interaction elucidates clinical observations correlating low estrogen receptor levels and elevated OVOL1 with worse prognoses, particularly in TNBC patients. These findings implicate hormonal milieu shifts, such as those occurring during menopause or weight gain, in modulating dormancy dynamics and recurrence risk.
The tantalizing implications extend to observed epidemiological patterns. Postmenopausal fat tissue becomes a significant source of estrogen production, potentially lowering OVOL1 levels systemically and thus awakening dormant tumor cells. This novel link may transform clinical management strategies for survivors by spotlighting weight management and hormone modulation as preventive measures against relapse. Prof. Yarden emphasizes the need for future animal and human studies to validate these hypotheses and develop targeted interventions that could block dormancy onset or tumor resurgence.
Central to the study’s groundbreaking contribution is its elucidation of the biochemical cascade triggered by OVOL1-induced dormancy. The research team identified an unexpected accumulation of reactive oxygen species—primarily free radicals—within dormant cancer cells. These unstable molecules induce extensive oxidative damage, disrupting DNA integrity and stalling the cell cycle, thereby enforcing the dormant state. Significantly, prior to this report, the involvement of oxidative stress in cancer cell dormancy had not been described, marking a paradigm shift in the understanding of tumor biology.
Continuing their investigation in collaboration with Prof. Emeritus Yosef Shiloh at Tel Aviv University, the researchers uncovered profound genomic consequences of sustained oxidative stress during dormancy. The delicate balance of nuclear proteins responsible for DNA repair becomes disrupted by oxidation, compromising the function of three critical repair factors. As a result, dormant cells accumulate a substantial mutational burden during their quiescent phase, an insight that challenges the classical notion of dormancy as mere cellular suspension and depicts it as an active phase of genetic evolution.
This accumulation of mutations appears to underlie the phenomenon of aggressive relapse after dormancy. When dormant cancer cells re-enter the cell cycle, their altered genome equips them with enhanced survival capabilities and resistance to conventional therapies. These findings may partly explain why recurrent breast tumors often defy standard treatment regimens and harbor more malignant traits compared to their primary counterparts.
Prof. Yarden calls attention to the translational potential of these discoveries, noting that dormancy is not unique to breast cancer but is a feature shared by many malignancies such as prostate and melanoma. By dissecting the molecular and biochemical underpinnings of dormancy, this research opens new avenues for intercepting cancer progression by either preventing dormancy induction or forestalling the reawakening of latent tumor cells. This strategical pivot could revolutionize cancer therapeutics by addressing one of the primary sources of treatment failure and mortality.
In conclusion, the intricate dance between epithelial and mesenchymal states in breast cancer cells, orchestrated by OVOL proteins and modulated by hormonal and oxidative forces, emerges as a critical determinant of cancer dormancy and relapse. The recognition that dormant cells accumulate DNA damage and evolve during their quiescent phase recasts dormancy as a dynamic, high-stakes biological state rather than a simple pause. These revelations not only deepen our grasp of tumor biology but also herald a future where managing dormancy could translate into prolonged remission and enhanced survival for breast cancer patients worldwide.
Subject of Research: Mechanisms of breast cancer cell dormancy and relapse with a focus on OVOL proteins, oxidative stress, and hormonal regulation.
Article Title: Re-epithelialization of cancer cells increases autophagy and DNA damage: Implications for breast cancer dormancy and relapse
News Publication Date: 22-Apr-2025
Web References:
Science Signaling DOI 10.1126/scisignal.ado3473
Keywords: Breast cancer, tumor tissue, discovery research, cellular proteins, mutant proteins, cellular processes, cancer research, breast cancer cells
