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.