Humoral Bone Morphogenetic Protein 2 Is Sufficient for Inducing Breast Cancer Microcalcification

Abstract

Microcalcifications are an important diagnostic marker for breast cancer on mammograms, yet the mechanism of their formation is poorly understood. Indeed, there is presently no short-latency, high-yield, syngeneic rodent model of the process. Bone morphogenetic protein 2 (BMP-2) is a key mediator of physiologic bone formation and pathologic vasculature calcification, but its role in breast cancer microcalcification is unknown. In this study, R3230 rat breast tumors were adapted to cell culture, transduced with adenoviral BMP-2, and inoculated into a syngeneic host. Tumor growth and calcium salt deposition were quantified in living animals over time using micro-computed tomography and probed chemically using near-infrared fluorescence. Plasma BMP-2 levels were quantified over time by enzyme-linked immunosorbent assay. Within 3 weeks, 100% of the breast tumors developed microcalcifications, which were absent from all normal tissues. Importantly, when two tumors were initiated in a single host, the ipsilateral tumor expressing BMP-2 was able to induce microcalcification in the contralateral tumor that was not expressing BMP-2, suggesting that BMP-2 can act humorally. Taken together, we describe the first reproducible rodent model of breast cancer microcalcification, prove that BMP-2 expression is sufficient for initiating the process, and lay the foundation for a new generation of targeted diagnostic agents.

Differences in the Pattern and Regulation of Mineral Deposition in Human Cell Lines of Osteogenic and Non-Osteogenic Origin

“…Indeed, the occurrence of mineral deposition outside of the normal osteogenic differentiation process has been observed in other contexts such as cancer. Cancer models and cell lines such as prostate or breast cancer cells are known to have osteomimetic properties, including upregulation of osteoblast-associated genes [Koeneman et al, 1999;Lin et al, 2001;Amatschek et al, 2004;Liu et al, 2008]. Adenomas and adenocarcinomas sometimes contain mineralized derivatives and calcium phosphate deposits with hydroxyapatite characteristics [Ilse et al, 1980;Andrews, 2002;Morgan et al, 2005], which would be compatible with our in vitro observation that non-osteogenic cells such as HeLa cells are capable of mineral deposition.…”

Controlled dual delivery of BMP-2 and dexamethasone by nanoparticle-embedded electrospun nanofibers for the efficient repair of critical-sized rat calvarial defect

“…Although BMP-2 has been widely studied and has been proven to be beneficial to the promotion of bone repair, excessive BMP-2 is thought to stimulate tumor growth [14,15]. In this study, we calculated the daily released quantity of BMP-2 from the in vitro release profile with an approximately zero-order release pattern.…”

Disruption of bone morphogenetic protein receptor 2 (BMPR2) in mammary tumors promotes metastases through cell autonomous and paracrine mediators

“…It has also been shown that, when breast cancer cell lines are treated with BMP4, they have enhanced migration and invasion (4,5,7,14). BMP2 has been shown to promote breast cancer microcalcification (15). BMP2 has been shown to induce tenascin-W, an ECM-related molecule found in advanced breast tumors (16).…”