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Open Access Highly Accessed Research article

Microcalcifications in breast cancer: an active phenomenon mediated by epithelial cells with mesenchymal characteristics

Manuel Scimeca1, Elena Giannini1, Chiara Antonacci1, Chiara Adriana Pistolese2, Luigi Giusto Spagnoli1 and Elena Bonanno1*

Author Affiliations

1 Anatomic Pathology Section, Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, Via Montpellier 1, Rome 00133, Italy

2 Diagnostic Imaging Section, Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, Via Montpellier 1, Rome 00133, Italy

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BMC Cancer 2014, 14:286  doi:10.1186/1471-2407-14-286

Published: 23 April 2014

Abstract

Background

Mammary microcalcifications have a crucial role in breast cancer detection, but the processes that induce their formation are unknown. Moreover, recent studies have described the occurrence of the epithelial–mesenchymal transition (EMT) in breast cancer, but its role is not defined. In this study, we hypothesized that epithelial cells acquire mesenchymal characteristics and become capable of producing breast microcalcifications.

Methods

Breast sample biopsies with microcalcifications underwent energy dispersive X-ray microanalysis to better define the elemental composition of the microcalcifications. Breast sample biopsies without microcalcifications were used as controls. The ultrastructural phenotype of breast cells near to calcium deposits was also investigated to verify EMT in relation to breast microcalcifications. The mesenchymal phenotype and tissue mineralization were studied by immunostaining for vimentin, BMP-2, β2-microglobulin, β-catenin and osteopontin (OPN).

Results

The complex formation of calcium hydroxyapatite was strictly associated with malignant lesions whereas calcium-oxalate is mainly reported in benign lesions. Notably, for the first time, we observed the presence of magnesium-substituted hydroxyapatite, which was frequently noted in breast cancer but never found in benign lesions. Morphological studies demonstrated that epithelial cells with mesenchymal characteristics were significantly increased in infiltrating carcinomas with microcalcifications and in cells with ultrastructural features typical of osteoblasts close to microcalcifications. These data were strengthened by the rate of cells expressing molecules typically involved during physiological mineralization (i.e. BMP-2, OPN) that discriminated infiltrating carcinomas with microcalcifications from those without microcalcifications.

Conclusions

We found significant differences in the elemental composition of calcifications between benign and malignant lesions. Observations of cell phenotype led us to hypothesize that under specific stimuli, mammary cells, which despite retaining a minimal epithelial phenotype (confirmed by cytokeratin expression), may acquire some mesenchymal characteristics transforming themselves into cells with an osteoblast-like phenotype, and are able to contribute to the production of breast microcalcifications.