Arsenic exposure induces stemness in human normal breast epithelial cells via the E2F2/FZD10 axis.

Chronic arsenic exposure is associated with systemic toxicity and carcinogenic risk, yet its mechanistic link to breast cancer remains poorly defined. Here, we demonstrate that long-term exposure of human mammary epithelial cells (MCF-10A) to low-dose sodium arsenite (NaAsO2) drives acquisition of a breast cancer stem-like phenotype. NaAsO2-exposed cells exhibited enhanced migration (1.34-fold), invasion (2.9-fold), and sphere-formation (1.54-fold) capacities, along with elevated expression of BCSCs markers EpCAM (3.17-fold) and ALDH1 (2.45-fold) and an increased CD44+/CD24-/low subpopulation (1.63-fold). Transcriptomic profiling identified the transcription factor E2F2 as a key mediator of this transformation. Functional studies established that E2F2 directly regulates FZD10 expression, activating the Wnt/β-catenin pathway to sustain the stem-like state. Collectively, we unveil the E2F2/FZD10 axis as a previously unrecognized molecular conduit through which environmental arsenic reprograms mammary epithelial cells toward a BCSCs-like phenotype, providing mechanistic insight into arsenic-associated breast cancer risk and revealing a potential target for preventive intervention.