CCN3 Impairs Osteoblast and Stimulates Osteoclast Differentiation to Favor Breast Cancer Metastasis to Bone

• DOI: 10.1016/j.ajpath.2011.01.033
• Publication Date: 2011-04-25T00:31:10Z
• Authors: Véronique Ouellet; Kerstin Tiedemann; Anna Mourskaia; Jenna E. Fong; Danh Tran-Thanh; Eitan Amir; Mark Clemons; Bernard Perbal; Svetlana V. Komarova; Peter M. Siegel
• Keywords: Osteoblasts; Reverse Transcriptase Polymerase Chain Reaction; Blotting, Western; Transplantation, Heterologous; Fluorescent Antibody Technique; Osteoclasts; Bone Neoplasms; Breast Neoplasms; Cell Differentiation; Enzyme-Linked Immunosorbent Assay; Microarray Analysis; Immunohistochemistry; 3. Good health; Mice; Nephroblastoma Overexpressed Protein; 03 medical and health sciences; 0302 clinical medicine; Animals; Humans; Female; Neoplasm Metastasis; Signal Transduction

Bone is a preferred site for breast cancer metastasis, causing pain, fractures, spinal cord compressions, and hypercalcemia, all of which can significantly diminish the patient's quality of life. We identified CCN3 as a novel factor that is highly expressed in bone metastatic breast cancer cells from a xenograft mouse model and in bone metastatic lesions from patients with breast cancer. We demonstrate that CCN3 overexpression enhances the ability of weakly bone metastatic breast cancer cells to colonize and grow in the bone without altering their growth in the mammary fat pad. We further demonstrated that human recombinant CCN3 inhibits osteoblast differentiation from primary bone marrow cultures, leading to a higher receptor activator of NF-κB ligand (RANKL)/osteoprotegerin (OPG) ratio. In conjunction with its ability to impair osteoblast differentiation, we uncovered a novel role for CCN3 in promoting osteoclast differentiation from RANKL-primed monocyte precursors. CCN3 exerts its pro-osteoclastogenic effects by promoting calcium oscillations and nuclear factor of activated T cells c1 (NFATc1) nuclear translocation. Together, these results demonstrate that CCN3 regulates the differentiation of bone resident cells to create a resorptive environment that promotes the formation of osteolytic breast cancer metastases.