Microcalcifications in breast cancer: novel insights into the molecular mechanism and functional consequence of mammary mineralisation

Abstract

Background:Mammographic microcalcifications represent one of the most reliable features of nonpalpable breast cancer yet remain largely unexplored and poorly understood.Methods:We report a novel model to investigate the in vitro mineralisation potential of a panel of mammary cell lines. Primary mammary tumours were produced by implanting tumourigenic cells into the mammary fat pads of female BALB/c mice.Results:Hydroxyapatite (HA) was deposited only by the tumourigenic cell lines, indicating mineralisation potential may be associated with cell phenotype in this in vitro model. We propose a mechanism for mammary mineralisation, which suggests that the balance between enhancers and inhibitors of physiological mineralisation are disrupted. Inhibition of alkaline phosphatase and phosphate transport prevented mineralisation, demonstrating that mineralisation is an active cell-mediated process. Hydroxyapatite was found to enhance in vitro tumour cell migration, while calcium oxalate had no effect, highlighting potential consequences of calcium deposition. In addition, HA was also deposited in primary mammary tumours produced by implanting the tumourigenic cells into the mammary fat pads of female BALB/c mice.Conclusion:This work indicates that formation of mammary HA is a cell-specific regulated process, which creates an osteomimetic niche potentially enhancing breast tumour progression. Our findings point to the cells mineralisation potential and the microenvironment regulating it, as a significant feature of breast tumour development.

An Approach to Breast Cancer Diagnosis via PET Imaging of Microcalcifications Using 18F-NaF

“…These calcium deposits are potentially the result of condensation of one of two types of microcalcification found within the tumor microenvironment: Type I which contains calcium oxalate dehydrate (CO), and Type II which contains calcium phosphates in the form of hydroxyapatite (HAP) 6 . Importantly, Type I deposits are associated with benign breast disease, while malignant cells have the unique capability to produce HAP 4, 7, 8 . Alkaline phosphatase (ALP) on the surface of malignant cells hydrolyses β-glycerophosphate (βG) to glycerol and inorganic phosphate (Pi), which is transported into the cell by the type II family of Na-Pi cotransporters.…”

“…HAP then leaves the cells, by unknown mechanisms, into the extracellular matrix. Furthermore, HAP enhances the mitogenesis of mammary cells which amplifes the malignant process resulting in accelerated tumor growth 7, 8 . Therefore, HAP may be a biomarker for breast malignancy.…”

Association between mammographic features and response to neoadjuvant chemotherapy in locally advanced breast carcinoma

“…18 They usually consist of carbonated calcium hydroxyapatite and their development appears to be a cell-specific regulated process that influences tumor behavior. 19 Our microcalcification prevalence (31.1%) is in the published range and is associated with the presence of an in situ component (p < 0.001). Some series have found an association between microcalcification and all high-grade histology, non-TN phenotype and a poor outcome in specific subsets.…”

Photoacoustic imaging of breast microcalcifications: A validation study with 3‐dimensional ex vivo data and spectrophotometric measurement

“…The mechanism of mammary mineralization and its influence on cancerous cell proliferation have not been fully understood, but it is known that the abnormal chemical circumstance of breast tissue, e.g., an overexpression of alkaline phosphatase (ALP) can accelerate the formation of breast microcalcifications [1,2]. Also, several studies have demonstrated that the microcalcifications is highly related to the development of breast tumor [1,3]. Therefore, if the microcalcifications are found in abnormal breast lesions through breast cancer screening, needle biopsy followed by histological examination is generally …”