Abstract
Metalloestrogens, metals and metalloids capable of mimicking or interfering with estrogen signaling, are emerging environmental contributors to breast cancer risk and endocrine therapy resistance. Compounds such as cadmium, arsenic, aluminum, and chromium bind to estrogen receptors or activate non-genomic pathways such as G protein-coupled estrogen receptor and epidermal growth factor receptor signaling, leading to aberrant proliferation, survival, and oxidative stress. These mechanisms promote epithelial–mesenchymal transition, genomic instability, and therapy resistance in estrogen receptor-positive breast cancer. Cadmium and arsenic can sustain estrogenic signaling and activate MAPK/ERK and PI3K/Akt pathways even under tamoxifen treatment, while arsenic-mediated BRCA1 methylation further reduces drug responsiveness. Limited studies suggest metalloestrogens may also attenuate the efficacy of aromatase inhibitors and selective estrogen receptor degraders by maintaining G protein-coupled estrogen receptor and oxidative stress signaling. Epidemiological evidence correlates elevated cadmium, nickel, and aluminum exposure with increased estrogen receptor-positive breast cancer incidence, yet clinical translation remains incomplete. Understanding metalloestrogen-mediated crosstalk between estrogen receptor-dependent and estrogen receptor-independent pathways will be essential for designing effective combination therapies and integrating environmental toxicology into precision breast cancer management.