Microcalcifications Drive Breast Cancer Occurrence and Development by Macrophage-Mediated Epithelial to Mesenchymal Transition

Abstract

Background: This study aims to investigate: (a) the putative association between the presence of microcalcifications and the expression of both epithelial-to-mesenchymal transition and bone biomarkers, (b) the role of microcalcifications in the breast osteoblast-like cells (BOLCs) formation, and (c) the association between microcalcification composition and breast cancer progression. Methods: We collected 174 biopsies on which we performed immunohistochemical and ultrastructural analysis. In vitro experiments were performed to demonstrate the relationship among microcalcification, BOLCs development, and breast cancer occurrence. Ex vivo investigations demonstrated the significant increase of breast osteoblast-like cells in breast lesions with microcalcifications with respect to those without microcalcifications. Results: In vitro data displayed that in the presence of calcium oxalate and activated monocytes, breast cancer cells undergo epithelial to mesenchymal transition. Also, in this condition, cells acquired an osteoblast phenotype, thus producing hydroxyapatite. To further confirm in vitro data, we studied 15 benign lesions with microcalcification from patients that developed a malignant condition in the same breast quadrant. Immunohistochemical analysis showed macrophages’ polarization in benign lesions with calcium oxalate. Conclusions: Altogether, our data shed new light about the role of microcalcifications in breast cancer occurrence and progression.