Pro-matrix metalloproteinase-2 transfection increases orthotopic primary growth and experimental metastasis of MDA-MB-231 human breast cancer cells in nude mice.
The ability to activate pro-matrix metalloproteinase (pro-MMP)-2 via membrane type-MMP is a hallmark of human breast cancer cell lines that show increased invasiveness, suggesting that MMP-2 contributes to human breast cancer progression. To investigate this, we have stably transfected pro-MMP-2 into the human breast cancer cell line MDA-MB-231, which lacks MMP-2 expression but does express its cell surface activator, membrane type 1-MMP. Multiple clones were derived and shown to produce pro-MMP-2 and to activate it in response to concanavalin A. In vitro analysis showed that the pro-MMP-2-transfected clones exhibited an increased invasive potential in Boyden chamber and Matrigel outgrowth assays, compared with the parental cells or those transfected with vector only. When inoculated into the mammary fat pad of nude mice, each of the MMP-2-tranfected clones grew faster than each of the vector controls tested. After intracardiac inoculation into nude mice, pro-MMP-2-transfected clones showed a significant increase in the incidence of metastasis to brain, liver, bone, and kidney compared with the vector control clones but not lung. Increased tumor burden was seen in the primary site and in lung metastases, and a trend toward increased burden was seen in bone, however, no change was seen in brain, liver, or kidney. This data supports a role for MMP-2 in breast cancer progression, both in the growth of primary tumors and in their spread to distant organs. MMP-2 may be a useful target for breast cancer therapy when refinement of MMP inhibitors provides for MMP-specific agents.
Tester
Angus M
AM
Victorian Breast Cancer Research Consortium (VBCRC) Invasion and Metastasis Unit, St. Vincent's Institute of Medical Research, Department of Surgery, University of Melbourne, Australia.
Waltham
Mark
M
Oh
Se-Jeong
SJ
Bae
Seog-Nyeon
SN
Bills
Margaret M
MM
Walker
Emma C
EC
Kern
Francis G
FG
Stetler-Stevenson
William G
WG
Lippman
Marc E
ME
Thompson
Erik W
EW
D000818:Animals; D001932:Brain Neoplasms / Q000473:pathology / Q000556:secondary; D001943:Breast Neoplasms / Q000473:pathology*; D002455:Cell Division / Q000235:genetics; D045744:Cell Line, Tumor; D004792:Enzyme Precursors / Q000235:genetics* / Q000378:metabolism; D005260:Female; D018093:Gelatinases / Q000235:genetics* / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007680:Kidney Neoplasms / Q000473:pathology / Q000556:secondary; D008113:Liver Neoplasms / Q000473:pathology / Q000556:secondary; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary; D008666:Metalloendopeptidases / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000473:pathology*; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection; D014183:Transplantation, Heterologous
D004792:Enzyme Precursors; D011994:Recombinant Proteins; D018093:Gelatinases; D008666:Metalloendopeptidases; C069860:progelatinase