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Short Hairpin RNA–Mediated Inhibition of Matrix Metalloproteinase-1 in MDA-231 Cells: Effects on Matrix Destruction and Tumor Growth

¹ Departments of Medicine and ² Biochemistry, Dartmouth Medical School, Hanover, New Hampshire and ³ Norris Cotton Cancer Center, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire

Requests for reprints: Constance E. Brinckerhoff, Dartmouth Hitchcock Medical Center, Norris Cotton Cancer Center, Room 602, Rubin Building, 1 Medical Center Drive, Lebanon, NH 03756. Phone: 603-653-9957; Fax: 603-653-9952; E-mail: brinckerhoff{at}dartmouth.edu.

Increased matrix metalloproteinase-1 (MMP-1) expression is associated with advanced stages of breast cancer and may be a predictive marker for the development of invasive disease. In this report, we used short hairpin RNA (shRNA) molecules to investigate whether MMP-1 production in MDA-231 breast cancer cells contributed to the degradation of a collagen matrix or tumor formation in nude mice. We created two groups of MDA-231 cell lines. MDA-231 cells containing a vector producing shRNA specific for MMP-1 had a >90% decrease in MMP-1 mRNA and protein compared with cells containing an empty vector, and blocking MMP-1 expression inhibited the in vitro collagenolytic activity of MDA-231 cells. When the cells were injected into the mammary fat pad, there was no difference in the frequency of tumor formation in mice. However, the average tumor size was larger in mice injected with cells containing the empty vector (1,216 ± 334 mm³) than in mice injected with cells expressing the MMP-1 shRNA (272 ± 117 mm³; P = 0.027). We conclude that MMP-1 expression is essential for the ability of MDA-231 cells to invade and destroy a collagen matrix and in vivo experiments suggest an important role for MMP-1 in breast tumor growth.

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