Genomic analysis of a spontaneous model of breast cancer metastasis to bone reveals a role for the extracellular matrix.
A clinically relevant model of spontaneous breast cancer metastasis to multiple sites, including bone, was characterized and used to identify genes involved in metastatic progression. The metastatic potential of several genetically related tumor lines was assayed using a novel real-time quantitative RT-PCR assay of tumor burden. Based on this assay, the tumor lines were categorized as nonmetastatic (67NR), weakly metastatic to lymph node (168FARN) or lung (66cl4), or highly metastatic to lymph node, lung, and bone (4T1.2 and 4T1.13). In vitro assays that mimic stages of metastasis showed that highly metastatic tumors lines were more adhesive, invasive, and migratory than the less metastatic lines. To identify metastasis-related genes in this model, each metastatic tumor was array profiled against the nonmetastatic 67NR using 15,000 mouse cDNA arrays. A significant proportion of genes relating to the extracellular matrix had elevated expression in highly metastatic tumors. The role of one of these genes, POEM, was further investigated in the model. In situ hybridization showed that POEM expression was specific to the tumor epithelium of highly metastatic tumors. Decreased POEM expression in 4T1.2 tumors significantly inhibited spontaneous metastasis to the lung, bone, and kidney. Taken together, our data support a role for the extracellular matrix in metastatic progression and describe, for the first time, a role for POEM in this process.
Eckhardt
Bedrich L
BL
Trescowthick Research Laboratories, Peter MacCallum Cancer Centre, Locked Bag 1, A'Beckett Street, Melbourne, Victoria, Australia 8006.
Parker
Belinda S
BS
van Laar
Ryan K
RK
Restall
Christina M
CM
Natoli
Anthony L
AL
Tavaria
Michael D
MD
Stanley
Kym L
KL
Sloan
Erica K
EK
Moseley
Jane M
JM
Anderson
Robin L
RL
D000818:Animals; D001859:Bone Neoplasms / Q000556:secondary*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D003094:Collagen / Q000737:chemistry; D004247:DNA / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D018450:Disease Progression; D004338:Drug Combinations; D005109:Extracellular Matrix / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D017403:In Situ Hybridization; D007797:Laminin / Q000737:chemistry; D008207:Lymphatic Metastasis; D051379:Mice; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic; D009693:Nucleic Acid Hybridization; D011509:Proteoglycans / Q000737:chemistry; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012235:Rhodamines / Q000494:pharmacology; D014018:Tissue Distribution
D018076:DNA, Complementary; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D012235:Rhodamines; C059485:matrigel; D049452:Green Fluorescent Proteins; C022027:lissamine rhodamine B; D003094:Collagen; D004247:DNA