Microcalcifications can either trigger or suppress breast precancer malignancy potential according to the mineral type in a 3D tumor model

Most early breast precancer lesions, termed ductal carcinoma in situ (DCIS), contain microcalcifications (MCs), which are calcium-containing pathological minerals. The most common type of MCs is calcium phosphate crystals, mainly carbonated apatite; it is associated with either benign or malignant lesions. In-vitro studies indicate that the crystal properties of apatite MCs can affect breast cancer progression. A less common type of MCs is calcium oxalate dihydrate (COD), which is almost always found in benign lesions. We developed a 3D tumor model of multicellular spheroids of human precancer cells containing synthetic MC analogs that link the crystal properties of MCs with the progression of breast precancer to invasive cancer. We show that apatite crystals induce proliferation and Her2 overexpression in DCIS cells. This tumor-triggering effect is increased when the carbonate fraction in the MCs decreases. COD crystals, in contrast, do not induce proliferation and reduce Her2 expression, even compared with control spheroids with no added MC analogs. This finding suggests that COD is not randomly located only in benign lesions--it may actively contribute to suppressing precancer progression in its surroundings. Our model provides an easy-to-manipulate platform to better understand the interactions between breast precancer cells and MCs. A better understanding of the effect of the crystal properties of MCs on precancer progression will potentially provide new directions for better precancer prognosis and treatment.