title: Osteoactivin promotes breast cancer metastasis to bone.
abstract: The skeleton is a preferred site of metastasis in patients with disseminated breast cancer. We have used 4T1 mouse mammary carcinoma cells, which metastasize to bone from the mammary fat pads of immunocompetent mice, to identify novel genes involved in this process. In vivo selection of parental cells resulted in the isolation of independent, aggressively bone metastatic breast cancer populations with reduced metastasis to the lung. Gene expression profiling identified osteoactivin as a candidate that is highly and selectively expressed in aggressively bone metastatic breast cancer cells. These cells displayed enhanced migratory and invasive characteristics in vitro, the latter requiring sustained osteoactivin expression. Osteoactivin depletion in these cells, by small interfering RNA, also lead to a loss of matrix metalloproteinase-3 expression, whereas forced osteoactivin expression in parental 4T1 cells was sufficient to elevate matrix metalloproteinase-3 levels, suggesting that this matrix metalloproteinase may be an important mediator of osteoactivin function. Overexpression of osteoactivin in an independent, weakly bone metastatic breast cancer cell model significantly enhanced the formation of osteolytic bone metastases in vivo. Finally, high levels of osteoactivin expression in primary human breast cancers correlate with estrogen receptor-negative status and increasing tumor grade. Thus, we have identified osteoactivin as a protein that is expressed in aggressive human breast cancers and is capable of promoting breast cancer metastasis to bone.
authors.affiliation: Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: April A N
authors.initials: AA
authors.lastname: Rose
authors.forename: François
authors.initials: F
authors.lastname: Pepin
authors.forename: Caterina
authors.initials: C
authors.lastname: Russo
authors.forename: Jad E
authors.initials: JE
authors.lastname: Abou Khalil
authors.forename: Michael
authors.initials: M
authors.lastname: Hallett
authors.forename: Peter M
authors.initials: PM
authors.lastname: Siegel
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D045744:Cell Line, Tumor; D002465:Cell Movement; D005136:Eye Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009361:Neoplasm Invasiveness; D034741:RNA, Small Interfering / Q000494:pharmacology
chemical_list: D005136:Eye Proteins; C445671:Gpnmb protein, mouse; D008562:Membrane Glycoproteins; D034741:RNA, Small Interfering