Upregulation of matrix metalloproteinases (MMPs) in breast cancer xenografts: a major induction of stromal MMP-13.
In human breast cancer (HBC), as with many carcinoma systems, most matrix metalloproteinases (MMPs) are largely expressed by the stromal cells, whereas the tumour cells are relatively silent in MMP expression. To determine the tissue source of the most relevant MMPs, we xenografted HBC cell lines and HBC tissues into the mammary fat pad (MFP) or bone of immunocompromised mice and measured the expression of human and mouse MMP-2, -9, -11, -13, membrane-type-1 MMP (MT1-MMP), MT2-MMP and MT3-MMP by species-specific real-time quantitative RT-PCR. Our data confirm a stromal origin for most tumour-associated MMPs and indicate marked and consistent upregulation of stromal (mouse) MMP-13 and MT1-MMP in all xenografts studied, irrespective of implantation in the MFP or bone environments. In addition, we show increased expression of both human MMP-13 and human MT1-MMP by the MDA-MB-231 tumour cells grown in the MFP compared to in vitro production. MMP protein and activity data confirm the upregulation of MMP mRNA production and indicate an increase in the activated MMP-2 species as a result of tumour implantation. These data directly demonstrate tumour induction of MMP production by stromal cells in both the MFP and bone environments. These xenografts are a valuable means for examining in vivo production of MMPs and suggest that MMP-13 and MT1-MMP will be relevant targets for inhibiting breast cancer progression.
Lafleur
Marc A
MA
VBCRC Invasion and Metastasis Group, St. Vincent's Institute, Fitzroy, Victoria, Australia.
Drew
Angela F
AF
de Sousa
Emma L
EL
Blick
Tony
T
Bills
Margaret
M
Walker
Emma C
EC
Williams
Elizabeth D
ED
Waltham
Mark
M
Thompson
Erik W
EW
D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D017364:Collagenases / Q000096:biosynthesis* / Q000378:metabolism*; D017931:DNA Primers / Q000737:chemistry; D018076:DNA, Complementary / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D006801:Humans; D053507:Matrix Metalloproteinase 11; D053509:Matrix Metalloproteinase 13; D053511:Matrix Metalloproteinase 14; D053517:Matrix Metalloproteinase 15; D053513:Matrix Metalloproteinase 16; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000096:biosynthesis / Q000378:metabolism; D000090023:Metallothionein 3; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D009368:Neoplasm Transplantation; D016133:Polymerase Chain Reaction; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
D017931:DNA Primers; D018076:DNA, Complementary; C507098:MMP15 protein, human; C507102:MMP16 protein, human; D000090023:Metallothionein 3; C507096:Mmp14 protein, mouse; C507100:Mmp15 protein, mouse; C507104:Mmp16 protein, mouse; C000715430:Mt3 protein, mouse; D012333:RNA, Messenger; D012313:RNA; D017364:Collagenases; C507079:MMP13 protein, human; D053507:Matrix Metalloproteinase 11; D053509:Matrix Metalloproteinase 13; D053517:Matrix Metalloproteinase 15; D053513:Matrix Metalloproteinase 16; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; C507081:Mmp13 protein, mouse; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D053511:Matrix Metalloproteinase 14