Matrix metalloproteinase 13 is induced in fibroblasts in polyomavirus middle T antigen-driven mammary carcinoma without influencing tumor progression.
Matrix metalloproteinase (MMP) 13 (collagenase 3) is an extracellular matrix remodeling enzyme that is induced in myofibroblasts during the earliest invasive stages of human breast carcinoma, suggesting that it is involved in tumor progression. During progression of mammary carcinomas in the polyoma virus middle T oncogene mouse model (MMTV-PyMT), Mmp13 mRNA was strongly upregulated concurrently with the transition to invasive and metastatic carcinomas. As in human tumors, Mmp13 mRNA was found in myofibroblasts of invasive grade II and III carcinomas, but not in benign grade I and II mammary intraepithelial neoplasias. To determine if MMP13 plays a role in tumor progression, we crossed MMTV-PyMT mice with Mmp13 deficient mice. The absence of MMP13 did not influence tumor growth, vascularization, progression to more advanced tumor stages, or metastasis to the lungs, and the absence of MMP13 was not compensated for by expression of other MMPs or tissue inhibitor of metalloproteinases. However, an increased fraction of thin collagen fibrils was identified in MMTV-PyMT;Mmp13(-/-) compared to MMTV-PyMT;Mmp13(+/+) tumors, showing that collagen metabolism was altered in the absence of MMP13. We conclude that the expression pattern of Mmp13 mRNA in myofibroblasts of invasive carcinomas in the MMTV-PyMT breast cancer model recapitulates the expression pattern observed in human breast cancer. Our results suggest that MMP13 is a marker of carcinoma-associated myofibroblasts of invasive carcinoma, even though it does not make a major contribution to tumor progression in the MMTV-PyMT breast cancer model.
Nielsen
Boye S
BS
The Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark.
Egeblad
Mikala
M
Rank
Fritz
F
Askautrud
Hanne A
HA
Pennington
Caroline J
CJ
Pedersen
Tanja X
TX
Christensen
Ib J
IJ
Edwards
Dylan R
DR
Werb
Zena
Z
Lund
Leif R
LR
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000494:pharmacology*; D017931:DNA Primers; D018450:Disease Progression; D005260:Female; D005347:Fibroblasts / Q000201:enzymology* / Q000821:virology*; D008175:Lung Neoplasms / Q000098:blood supply / Q000473:pathology / Q000556:secondary; D015674:Mammary Neoplasms, Animal / Q000098:blood supply / Q000201:enzymology* / Q000473:pathology*; D053509:Matrix Metalloproteinase 13 / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009389:Neovascularization, Pathologic
D000952:Antigens, Polyomavirus Transforming; D017931:DNA Primers; D053509:Matrix Metalloproteinase 13