Humoral bone morphogenetic protein 2 is sufficient for inducing breast cancer microcalcification.
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.
Liu
Fangbing
F
Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Bloch
Nathalie
N
Bhushan
Kumar R
KR
De Grand
Alec M
AM
Tanaka
Eiichi
E
Solazzo
Stephanie
S
Mertyna
Pawel M
PM
Goldberg
Nahum
N
Frangioni
John V
JV
Lenkinski
Robert E
RE
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D001940:Breast / Q000473:pathology; D002114:Calcinosis / Q000378:metabolism* / Q000473:pathology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344; D013050:Spectrometry, Fluorescence; D019265:Spectroscopy, Near-Infrared; D014054:Tomography; D014161:Transduction, Genetic; D014185:Transplantation, Isogeneic; D014407:Tumor Cells, Cultured
C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; C485192:green fluorescent protein, Aequorea victoria; D049452:Green Fluorescent Proteins