Abstract
IntroductionBreast microcalcifications is a characteristic feature in diagnostic imaging and a prognostic factor of breast cancer. However, the underlying mechanisms of breast microcalcifications formation are not fully understood. Previous studies have shown that upregulation of bone morphogenetic protein 2 (BMP-2) is associated with the occurrence of microcalcifications and tumor-associated macrophages (TAMs) in the tumor microenvironment can secrete BMP-2. The aim of this study is to elucidate the role of secretion of BMP-2 by TAMs in promoting microcalcifications of breast cancer through immunohistochemical staining and co-culturing of breast cancer cells with TAMs.MethodsA total of 272 patients diagnosed with primary invasive breast cancer from January 2010 to January 2012 in the First Hospital of China Medical University were included in this study. Immunohistochemical staining of CD68 (marker of entire macrophages), CD168 (marker of the M2-like macrophages) and BMP-2 were performed on 4-μm tissue microarray (TMA) sections. Following induction, THP-1 cells were differentiated to M2-like TAMs and were then co-cultured with breast cancer cells (MCF-7). Calcifications and BMP-2 expression were analyzed by Alizarin Red S staining and western blot, respectively.ResultsImmunohistochemical analysis showed that the expression of CD168 was significantly increased in tissues with microcalcifications and was correlated with the expression of BMP-2 and poor prognosis. The formation of cellular microcalcifications and BMP-2 expression were significantly increased in MCF-7 cells co-cultured with TAMs compared with MCF-7 cells alone.ConclusionsThese findings support the hypothesis that TAMs secrete BMP-2 to induce microcalcifications in breast cancer cells and influence prognosis via multiple pathways including BMP-2 and its downstream factors.
Highlights
Breast microcalcifications is a characteristic feature in diagnostic imaging and a prognostic factor of breast cancer
Immunohistochemical analysis showed that the expression of CD168 was significantly increased in tissues with microcalcifications and was correlated with the expression of bone morphogenetic protein 2 (BMP-2) and poor prognosis
The formation of cellular microcalcifications and BMP-2 expression were significantly increased in MCF-7 cells co-cultured with Tumor-associated macrophages (TAMs) compared with MCF-7 cells alone
Summary
Breast microcalcifications is a characteristic feature in diagnostic imaging and a prognostic factor of breast cancer. Previous studies have shown that upregulation of bone morphogenetic protein 2 (BMP-2) is associated with the occurrence of microcalcifications and tumor-associated macrophages (TAMs) in the tumor microenvironment can secrete BMP-2. Tumor-associated macrophages (TAMs) are one of the major types of tumor infiltrating immune cells in the extracellular environment [8] and were shown to accumulate around microcalcifications in breast cancer [9]. Most TAMs have M2-like phenotype (CD163) [17] and breast cancer cells can secrete factors to promote macrophage differentiation toward the M2-like phenotype [18]. CD68, a pan-macrophage marker, can be used as an effective indicator for both M1 and M2 macrophages [19], whereas the CD168 is a scavenger receptor specific to the M2 macrophages [20]
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