Osteomimetic microcalcification shapes the breast tumor microenvironment and metastatic potential.

Abstract

Microcalcifications are among the most reliable mammographic signs of breast cancer, particularly of non-palpable and in situ disease, yet for decades they were regarded as inert by-products of cellular degeneration-a view that delayed inquiry into their biology. A growing body of in vitro, ex vivo, and tissue-based evidence now reframes breast microcalcification as a process that can be actively regulated and cell-driven, recapitulating physiological and pathological mineralization elsewhere in the body. In this review, we synthesize the mechanistic basis of this paradigm shift and argue that mineral formation is not a passive marker but a participant in tumor biology. Two mineral species-calcium oxalate and calcium hydroxyapatite-carry different biological meaning and are separable on routine histopathology by birefringence and histochemistry. Hydroxyapatite can promote proliferation, matrix remodeling, and invasion, yet it is also the mineral of most benign calcifications, so its significance lies in composition and cellular origin, not presence alone. We discuss the osteomimetic program through which mammary tumor cells acquire bone-like mineralizing capacity, including the roles of alkaline phosphatase activity, ion transport, and PI3K-Akt signaling, and we distinguish osteomimicry-a phenotype of the tumor cell-from the bone metastatic niche that such cells may exploit. We then consider how mineral composition and microstructure encode the surrounding microenvironment and connect to clinical observations: association with HER2-positive disease, behavior under neoadjuvant chemotherapy, prognostic associations, and an emerging link with bone metastasis. We close with an integrated framework and a research agenda positioning mineral biology at the interface of the tumor microenvironment and metastatic progression.