Stimulation of mammary tumorigenesis by systemic tissue inhibitor of matrix metalloproteinase 4 gene delivery.
Tissue inhibitors of matrix metalloproteinase (TIMPs) are multifunctional proteins with both matrix metalloproteinase (MMP) inhibitory effects and growth-regulatory activity. TIMPs inhibit MMP activity, suggesting a use for cancer gene therapy. However, here we report that systemic administration of human TIMP-4 by electroporation-mediated i.m. injection of naked TIMP-4 DNA stimulates tumorigenesis of human breast cancer cells in nude mice. Consistent with tumor stimulation, TIMP-4 up-regulates Bcl-2 and Bcl-X(L) protein. TIMP-4 also inhibits apoptosis in human breast cancer cells in vitro and mammary tumors in vivo. A synthetic MMP inhibitor BB-94 did not have such antiapoptotic effect. Analysis of TIMP-4 expression in human mammary specimens indicates that TIMP-4 protein is increased in mammary carcinoma cells compared with normal mammary epithelial cells. These data indicate an antiapoptotic activity in breast cancer cells and a tumor-stimulating effect of TIMP-4 when administrated systemically.
Jiang
Y
Y
Department of Radiation Oncology, Long Island Jewish Medical Center, The Long Island Campus for Albert Einstein College of Medicine, New Hyde Park, New York 11040, USA.
Wang
M
M
Celiker
M Y
MY
Liu
Y E
YE
Sang
Q X
QX
Goldberg
I D
ID
Shi
Y E
YE
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001940:Breast / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002470:Cell Survival / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004247:DNA / Q000008:administration & dosage* / Q000235:genetics; D018274:Electroporation; D005260:Female; D015316:Genetic Therapy; D006801:Humans; D007273:Injections, Intramuscular; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010957:Plasmids / Q000008:administration & dosage / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D011817:Rabbits; D019714:Tissue Inhibitor of Metalloproteinases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014183:Transplantation, Heterologous; D051020:bcl-X Protein; D000097792:Tissue Inhibitor of Metalloproteinase-4
D004247:DNA; D019253:Proto-Oncogene Proteins c-bcl-2; D019714:Tissue Inhibitor of Metalloproteinases; D051020:bcl-X Protein; D000097792:Tissue Inhibitor of Metalloproteinase-4; C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse