Decoding the adaptive survival mechanisms of breast cancer dormancy

Abstract

Breast cancer (BC) recurrence remains a major clinical challenge, leaving patients in perpetual uncertainty about disease relapse after primary treatment. BC dormancy, an adaptive survival state of disseminated tumour cells, is a key driver of both early and late recurrence. However, the mechanisms regulating BC dormancy remain poorly understood. Emerging evidence suggests that tumour hypoxia, extracellular matrix (ECM) remodelling, and therapy-induced stress drive dormancy by altering cellular metabolism, gene expression, and immune interactions, enabling long-term survival of dormant BC cells. With no dormancy-specific therapies currently approved, a deeper understanding of dormancy-associated survival mechanisms is crucial for identifying therapeutic targets and developing strategies to eradicate dormant BC cells, thereby preventing recurrence and improving patient outcomes. This review comprehensively examines major dormancy-inducing factors and the adaptive survival mechanisms of dormant BC cells. We also highlight critical gaps in preclinical models that hinder the translation of preclinical cancer dormancy insights into clinical applications and propose potential therapeutic strategies to prevent BC recurrence.

Fig. 1. Overview of how breast cancer dormancy fuels recurrence.

The emergence of dormant breast cancer (BC) cell populations occurs as an adaptive response to dormancy-inducing stressors within the primary tumour microenvironment, including hypoxia, extracellular matrix (ECM) remodelling, and anti-cancer therapies. Dormant disseminated tumour cells (DTCs) employ various survival mechanisms, mainly DNA damage repair, autophagy, immune evasion, and transcriptional and epigenetic reprogramming. These adaptations enable dormant DTCs to persist undetected in circulation while remaining biologically active. Upon reaching various metastatic niches, such as the bone (most common), lungs, liver, and brain, disseminated tumour cells (DTCs) may encounter specialised microenvironments that provide dormancy-supporting signals. These cues enable DTCs to persist in a quiescent state for extended periods. However, in response to reactivation signals such as inflammation, niche remodelling, or immunosuppression, DTCs can exit dormancy, resume proliferation, and give rise to overt metastases, ultimately leading to disease relapse. Although several potential therapeutic strategies have been suggested and are currently being attempted [185], we suggest that targeting the survival mechanisms sustaining BC dormancy holds significant promise for preventing recurrence.

Fig. 2. Tumour hypoxia as a major inducer of breast cancer dormancy.

Hypoxia is a key driver of breast cancer (BC) dormancy. The presence of hypoxic subregions within the primary tumour is a common feature of BC, arising due to rapid tumour growth exceeding angiogenesis and leading to insufficient oxygen supply. Through both HIF-1α-dependent and independent signalling pathways, hypoxia primes BC cells with stress-adaptive mechanisms that enhance their resilience and survival. This adaptation contributes to the survival of dormant BC cells in the bone marrow, a naturally hypoxic microenvironment. Hypoxia-primed BC cells exhibit a dormant phenotype (G0/G1 arrest) with increased expression of dormancy-associated genes such as NR2F1, DEC2, and post-translational events like pRb, along with activation of the NRF2 oxidative stress response. The well-established link between hypoxia and BC dormancy in disseminated tumour cells (DTCs) may explain the poor prognosis and aggressive recurrence commonly observed in hypoxic BC cases.

Fig. 3. Extracellular matrix (ECM) remodelling and interaction with BC cells induce dormancy.

As a major component of the tumour microenvironment, the extracellular matrix (ECM), particularly collagen (Col-3) and fibronectin, plays a pivotal role in inducing dormancy in breast cancer (BC). ECM remodelling in the primary tumour enhances BC cell dormancy through the activation of STAT signalling and ERK/p38 pathways. In addition, collagen-rich ECM, commonly found in tumour hypoxia, increases ECM stiffness. This stiffness restricts cancer cell proliferation by mechanically confining the cells within a limited microenvironment, thereby increasing mechanical stress, which promotes an adaptive dormant state in breast cancer (BC) cells. Thus, the ECM-induced dormancy is considered as an adaptive state of BC cells in response to mechanical stress originating from the tumour microenvironment.

Fig. 4. Hallmarks of adaptive survival mechanisms in dormant breast cancer.

This summarizes five major adaptive survival mechanisms employed by dormant breast cancer cells. These mechanisms enable the cells to endure extended periods of dormancy and facilitate recurrence when environmental conditions change. Importantly, the mechanisms are not mutually exclusive but are likely to converge on a common intersecting pathway.