Vincenti MP and Brinckerhoff CE. Signal transduction and cell-type specific regulation of matrix metalloproteinase gene expression: Can MMPs be good for you?J Cell Physiol. 213:355-364, 2007.
Blackburn JS, Rhodes CH, Coon CI and Brinckerhoff CE. RNAi inhibition of MMP-1 prevents melanoma metastasis by reducing tumor collagenase activity and angiogenesis. Cancer Res. 67:10849-10858, 2007
Petrella BL, Lohi J and Brinckerhoff CE. Identification of membrane type-1
matrix metalloproteinase as a target of hypoxia-inducble factor 2alpha in
von Hippel-Lindau renal cell carcinoma. Oncogene 24: 1043-1053, 2005
Wyatt CW, Geoghegan JC and Brinckerhoff CE. Short hairpin RNA mediated
inhibition of Matrix Metalloproteinase-1 in MDA-231 cells: effects on matrix
destruction and tumor growth .Cancer Research.65: 11101-11108, 2005
Huntington JT, Shields JM, Der CJ, Wyatt CA, Benbow U, Slingluff CL and
Brinckerhoff CE. Overexpression of collagenase 1 (MMP-1) is mediated by the
ERK pathway in invasive melanoma cells: role of BRAF mutation and FGF
signaling. J. Biol. Chem. 279: 33168-33176, 2004
Research / Lab Interests
Our laboratory is investigating novel roles for matrix metalloproteinases
(MMPs) in tumor invasion and metastasis.
Our work on MMPs in melanoma began with identification of two molecular
markers for invasive/metastatic malignant melanoma: the “2G single
nucleotide polymorphism” (ETS site) in the MMP-1 promoter and the BRAF
mutation, which constitutively signals through the ERK pathway to target the
ETS site in the MMP-1 promoter, enhancing MMP-1 expression and the potential
for invasion. (JBC, 2004). More recent work indicates that MMP-1 expression
is required for THE melanoma cells metastasizing to the lung in a process
mediated by MMP-1 cleavage of Protease Activated Receptor-1 (PAR-1). With
the use of the NCCC Microarray Core, we have determined the global changes
in gene expression that depend on MMP-1 expression.
With the support of NCCC discretionary funds and the use of the NCCC
Research Pathology Shared Resource, we developed a new project on MMPs in
breast cancer with the observation that MMP-1 expression contributes to
breast tumor formation in a murine xenograft model (Cancer Res. 2005). We
are extending this work by developing an in vivo invasion model with MMP-1
knockdown cells in tumor cells are injected in the leg and monitored for
invasion and degradation of bone. Cells expressing the MMP-1 shRNA fail to
invade into bone, while cells with the control shRNA readily invade and
degrade bone. This may be of particular interest in breast cancer patients
whose disease invades the chest wall and ribs.
Additionally, we are studying the role of stromal/tumor cell interactions in
breast cancer. Cancer associated fibroblasts (CAFs) are commonly isolated
from tumors, but the mechanisms behind their induction are not known. We
are finding that some human breast tumors are not tumorigenic in nude mice
unless co-injected with human stromal fibroblasts. In this system, the tumor
cells do not produce MMPs, but do induce MMP production by the stromal
cells.
Grants, Honors, Invited Lectures
Executive Editor, J. Cellular Physiology
Recipient of Smith College Medal for Distinction in Teaching and Research
