Matrix metalloproteinase 13 is induced in fibroblasts in polyomavirus middle T antigen-driven mammary carcinoma without influencing tumor progression

Boye S Nielsen; Mikala Egeblad; Fritz Rank; Hanne A Askautrud; Caroline J Pennington; Tanja X Pedersen; Ib J Christensen; Dylan R Edwards; Zena Werb; Leif R Lund

doi:10.1371/journal.pone.0002959

Matrix metalloproteinase 13 is induced in fibroblasts in polyomavirus middle T antigen-driven mammary carcinoma without influencing tumor progression

Boye S Nielsen, Mikala Egeblad, Fritz Rank, Hanne A Askautrud, Caroline J Pennington, Tanja X Pedersen, Ib J Christensen, Dylan R Edwards, Zena Werb, Leif R Lund

23 Citations (Scopus)

Abstract

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.

Original language	English
Journal	PLoS ONE
Volume	3
Issue number	8
Pages (from-to)	e2959
ISSN	1932-6203
DOIs	https://doi.org/10.1371/journal.pone.0002959
Publication status	Published - 2008

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Nielsen, B. S., Egeblad, M., Rank, F., Askautrud, H. A., Pennington, C. J., Pedersen, T. X., Christensen, I. J., Edwards, D. R., Werb, Z., & Lund, L. R. (2008). Matrix metalloproteinase 13 is induced in fibroblasts in polyomavirus middle T antigen-driven mammary carcinoma without influencing tumor progression. PLoS ONE, 3(8), e2959. https://doi.org/10.1371/journal.pone.0002959

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title = "Matrix metalloproteinase 13 is induced in fibroblasts in polyomavirus middle T antigen-driven mammary carcinoma without influencing tumor progression",

abstract = "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.",

author = "Nielsen, {Boye S} and Mikala Egeblad and Fritz Rank and Askautrud, {Hanne A} and Pennington, {Caroline J} and Pedersen, {Tanja X} and Christensen, {Ib J} and Edwards, {Dylan R} and Zena Werb and Lund, {Leif R}",

note = "Keywords: Animals; Antigens, Polyomavirus Transforming; DNA Primers; Disease Progression; Female; Fibroblasts; Lung Neoplasms; Mammary Neoplasms, Animal; Matrix Metalloproteinase 13; Mice; Mice, Knockout; Neoplasm Metastasis; Neoplasm Staging; Neovascularization, Pathologic",

year = "2008",

doi = "10.1371/journal.pone.0002959",

language = "English",

volume = "3",

pages = "e2959",

journal = "PLoS Computational Biology",

issn = "1932-6203",

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T1 - Matrix metalloproteinase 13 is induced in fibroblasts in polyomavirus middle T antigen-driven mammary carcinoma without influencing tumor progression

AU - Nielsen, Boye S

AU - Egeblad, Mikala

AU - Rank, Fritz

AU - Askautrud, Hanne A

AU - Pennington, Caroline J

AU - Pedersen, Tanja X

AU - Christensen, Ib J

AU - Edwards, Dylan R

AU - Werb, Zena

AU - Lund, Leif R

N1 - Keywords: Animals; Antigens, Polyomavirus Transforming; DNA Primers; Disease Progression; Female; Fibroblasts; Lung Neoplasms; Mammary Neoplasms, Animal; Matrix Metalloproteinase 13; Mice; Mice, Knockout; Neoplasm Metastasis; Neoplasm Staging; Neovascularization, Pathologic

PY - 2008

Y1 - 2008

N2 - 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.

AB - 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.

U2 - 10.1371/journal.pone.0002959

DO - 10.1371/journal.pone.0002959

M3 - Journal article

C2 - 18698413

SN - 1932-6203

VL - 3

SP - e2959

JO - PLoS Computational Biology

JF - PLoS Computational Biology

IS - 8

ER -

Matrix metalloproteinase 13 is induced in fibroblasts in polyomavirus middle T antigen-driven mammary carcinoma without influencing tumor progression

Abstract

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