Matrix metalloproteinase (MMP)-13 regulates mammary tumor-induced osteolysis by activating MMP9 and transforming growth factor-beta signaling at the tumor-bone interface.
The tropism of breast cancer cells for bone and their tendency to induce an osteolytic phenotype are a result of interactions between breast cancer cells and stromal cells and are of paramount importance for bone metastasis. However, the underlying molecular mechanisms remain poorly understood. We hypothesize that tumor-stromal interaction alters gene expression in malignant tumor cells and stromal cells creating a unique expression signature that promotes osteolytic breast cancer bone metastasis and that inhibition of such interactions can be developed as targeted therapeutics. Microarray analysis was performed to investigate gene expression profiling at the tumor-bone (TB) interface versus the tumor alone area from syngenic mice injected with three different syngenic mammary tumor cell lines that differ in their metastatic potential. We identified matrix metalloproteinase 13 (MMP13), receptor activator of NF-kappaB ligand (RANKL), and integrins binding sialoprotein to be genes upregulated at the TB interface and validated. To determine the functional role of MMP13 in tumor-induced osteolysis, mice with Cl66 mammary tumors were treated with MMP13 antisense oligonucleotides (MMP13-ASO) or control scrambled oligonucleotides (control-ASO). Knockdown of MMP13 expression at the TB interface leads to significant reduction in bone destruction and in the number of activated osteoclasts at the TB interface. Further analysis to evaluate the mechanism of MMP13-dependent osteolytic bone metastasis revealed that MMP13-ASO treatment decreased active MMP9, RANKL levels, and transforming growth factor-beta signaling at the TB interface. Together, our data indicate that upregulation of MMP13 at the TB interface is important in tumor-induced osteolysis and suggest that MMP13 is a potential therapeutic target for breast cancer bone metastasis.
Nannuru
Kalyan C
KC
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198-5900, USA.
Futakuchi
Mitsuru
M
Varney
Michelle L
ML
Vincent
Thomas M
TM
Marcusson
Eric G
EG
Singh
Rakesh K
RK
D000230:Adenocarcinoma / Q000201:enzymology / Q000473:pathology; D000818:Animals; D001859:Bone Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000556:secondary*; D001842:Bone and Bones / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D005260:Female; D020869:Gene Expression Profiling; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D053509:Matrix Metalloproteinase 13 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008807:Mice, Inbred BALB C; D010010:Osteoclasts / Q000201:enzymology / Q000473:pathology; D010014:Osteolysis / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053244:Osteoprotegerin / Q000096:biosynthesis; D053245:RANK Ligand / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D015854:Up-Regulation
D061965:Matrix Metalloproteinase Inhibitors; D053244:Osteoprotegerin; D053245:RANK Ligand; D012333:RNA, Messenger; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse; D016212:Transforming Growth Factor beta; D053509:Matrix Metalloproteinase 13; D020780:Matrix Metalloproteinase 9
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