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Bonfiglio et al. J Cancer Metastasis Treat 2019;5:29 I http://dx.doi.org/10.20517/2394-4722.2018.88 Page 5 of 7

P = 0.0030
Positive cells/500

P = 0.0024
Positive cells/500

Figure 2. Immunohistochemical analysis of bone morphogenetic proteins 2 (BMP-2) and pentraxin-3 (PTX3). A: Graph shows the
number of BMP-2 positive breast cancer cells in BM+ and BM- patients; B: representative image of BMP-2 expression in a ductal
infiltrating breast carcinoma; C: graph shows the number of PTX3 positive breast cancer cells in BM+ and BM- patients; D: image displays
the PTX3 expression in a case of ductal infiltrating breast carcinoma. Scala bars represent 100 μm for all images

[7]
BOLCs) able to product microcalcifications made of HA or MgHAp . Noteworthy, the breast cancer lesions
[7]
characterized by the presence of BOLCs showed high propensity to form bone metastasis . Thus, the
presence of microcalcifications in breast lesions could represent a negative prognostic marker for metastatic
diseases. Starting from these considerations, the aim of this study was to correlate the microcalcifications’
characteristics, such as morphology and elemental compositions, with the occurrence of bone metastatic
lesions at 5 years from diagnosis. To this end, we retrospectively collected breast cancer lesions of patients
with (BM+) or without (BM-) clinical evidence of bone metastatic lesions. Our results clearly indicate that
elemental composition, but not morphological appearance, of breast microcalcifications can predict the
presence or development of bone metastatic lesions. In particular, according with the data reported by
[15]
Bonfiglio et al. , in this study the breast cancer lesions of BM+ patients were frequently characterized by
the presence calcifications made of MgHAp. Thus, the presence of MgHAp could play an active role in
breast cancer progression. Indeed, as hypothesized in our previously study, the ability of HA to bind Mg
can support the neoplastic progression by inhibiting the activity of DNA repair enzymes that require Mg as
co-factor. These data further support the hypothesis that the bone metastatic process of breast cancer can
be driven by BOLCs. Indeed, we also noted that breast cancer cells of BM+ patients acquired the capability
to express two of the most important osteoblast induction factors such as BMP-2 and PTX3. BMP-2 is a
[8]
member of TGF-β superfamily that which regulate numerous process in bone metabolisms . Specifically,
[8]
BMP-2 is involved in both mesenchymal stem cells recruitment and differentiation into mature osteoblasts .
[7]
In a recent paper, Scimeca et al. demonstrated the expression of BMP-2 by BOLCs. PTX3, also known as
TNF-inducible gene 14 protein, is a molecule involved in several process of innate immunity [17,18] . It is also
[9]
demonstrated that PTX3 have a role in the extracellular matrix formation as well as bone formation . In