title: CCN3 impairs osteoblast and stimulates osteoclast differentiation to favor breast cancer metastasis to bone.
abstract: 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.
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.
authors.forename: Véronique
authors.initials: V
authors.lastname: Ouellet
authors.forename: Kerstin
authors.initials: K
authors.lastname: Tiedemann
authors.forename: Anna
authors.initials: A
authors.lastname: Mourskaia
authors.forename: Jenna E
authors.initials: JE
authors.lastname: Fong
authors.forename: Danh
authors.initials: D
authors.lastname: Tran-Thanh
authors.forename: Eitan
authors.initials: E
authors.lastname: Amir
authors.forename: Mark
authors.initials: M
authors.lastname: Clemons
authors.forename: Bernard
authors.initials: B
authors.lastname: Perbal
authors.forename: Svetlana V
authors.initials: SV
authors.lastname: Komarova
authors.forename: Peter M
authors.initials: PM
authors.lastname: Siegel
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000378:metabolism* / Q000556:secondary; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D046228:Microarray Analysis; D009362:Neoplasm Metastasis / Q000473:pathology*; D055514:Nephroblastoma Overexpressed Protein / Q000378:metabolism*; D010006:Osteoblasts / Q000166:cytology*; D010010:Osteoclasts / Q000166:cytology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D014183:Transplantation, Heterologous
chemical_list: C526319:CCN3 protein, human; D055514:Nephroblastoma Overexpressed Protein