FOXM1 as a candidate dosage rheostat and state selector in breast cancer: linking multilevel regulation to adaptive plasticity and therapy resistance

Abstract

FOXM1, a forkhead-box transcription factor, is consistently overexpressed in breast cancer, particularly in the basal-like and triple-negative subtypes, in which high expression predicts poor survival. We propose, as a falsifiable hypothesis rather than an established mechanism, that FOXM1 may function as a dosage-integrating rheostat, in which convergent genomic, transcriptional, epitranscriptomic, translational, and post-translational inputs would determine discrete output states involving mitotic fidelity, chromosomal instability, metabolic rewiring, immune evasion, and stem-like plasticity. We further hypothesized that therapies directed elsewhere in the network are frequently buffered by the persistence or reactivation of FOXM1-associated outputs, while noting that resistance to direct FOXM1 inhibition proceeds instead through reversal of that output, which bounds the hypothesis rather than supporting it. Accordingly, we classified FOXM1-directed strategies, including direct inhibitors, degraders, condensate disruptors, upstream suppressors, and targeted delivery platforms, by their mechanism of engagement rather than by their chemical class. Existing evidence remains largely correlative and bulk-derived: available perturbation studies are categorical rather than graded, no study has titrated FOXM1 through intermediate levels or measured its outputs bidirectionally, and the few single-cell, time-resolved datasets resolve one output at a time. We identified these gaps, specified the components of an isoform-, localisation- and activation-resolved FOXM1 activity metric that would define dose in measurable terms, and proposed experiments to test threshold-dependent activation, discrete single-cell states, and history-dependent switching, grounding the last of these in the material properties and physical ageing of FOXM1 condensates rather than in an equilibrium phase boundary alone in order to distinguish dosage-dependent state selection from regulatory hub behavior.