Correspondence: Beyond phenotypic observations: elucidating the molecular drivers of hypoxia-reoxygenation-induced aggressiveness in breast cancer.

In their recent study, Maniar et al. demonstrated context-dependent phenotypic effects of hypoxia-reoxygenation in breast cancer cell lines [1]. These included enhanced proliferation, invasion, clonogenicity, and chemoresistance. While these findings provide important insights into tumor adaptation under fluctuating oxygen conditions, several mechanistic aspects remain insufficiently explored. In this correspondence, we highlight the absence of molecular characterization of hypoxia-inducible factor (HIF) signaling, despite its central role in mediating hypoxic responses. We also discuss the lack of direct assessment of reactive oxygen species (ROS), which were proposed as key drivers of the observed phenotypic changes. Also, the increase in migration and clonogenicity suggests the potential involvement of epithelial-mesenchymal transition (EMT) which was not evaluated. Finally, we mention the limitations of two-dimensional culture models and the potential value of three-dimensional systems in improving translational relevance.