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Symposium 10: Inflammation and Cancer

Breast cancer, MMPs, and inflammatory signals

Lawrence Berkeley National Laboratory, Berkeley, CA

Abstract

SY10-1

We now know that the microenvironment regulates normal homeostasis and contributes to inducting and promoting signals in cancer. Basement membrane (BM), but principally laminin-1, is involved in signaling to normal breast structure and hence function (Gudjonsson et al., 2002). Destruction of BM by metalloproteinases (MMPs) in transgenic animals disrupts functional differentiation, induces inflammation and eventually leads to mammary cancers (Sympson et al., 1995; Thomasset et al., 1998; Sternlicht et al., 1999). We had shown previously that conditional expression of MMP-3 in SCp2 mouse mammary epithelial cells, leads to epithelial mesenchymal transition (EMT) and eventually mammary cancer (Lochter et al., 1997; Sternlicht et al. 1999). I will discuss the possible mechanisms by which MMP-3 could induce genomic instability, inflammation, and cancer in both rodent and human models. In p53-negative SCp2 cells, we have shown that addition of exogenous MMP-3 or its conditional expression leads to concomitant EMT and genomic instability through induction of reactive oxygen species (ROS). I will discuss the mechanism by which MMP-3 may induce ROS. In EPH4 mouse mammary cells which are p53 positive, MMP-3 causes cell death. In human breast epithelial MCF-10A cells, addition of recombinant MMP-3 causes rapid cell contraction, membrane blebbing, loss of E-cadherin, p38 activation and an increase in p53 protein levels. We now know that MMP-3-induced membrane blebbing is suppressed by inhibiting different components of the TNF-superfamily signaling cascade, such as JNK and FADD. These findings indicate MMP-3 may act as a pro-inflammatory factor under certain conditions and offer a possible explanation of why mammary inflammation was prominent in our MMP-3 transgenic mice (Thomasset et al., 1998). In addition, we have shown that malignant breast epithelial cells may be reverted to a normal polar phenotype by modulating microenvironmental signaling in 3D, that resistance to chemotherapy is very much a function of tissue polarity and environmental control (Weaver et al, 1997; Weaver et al., 2002; Wang et al., 1998; Wang et al., 2003; Liu et al., 2004; for review see Bissell et al., 2003). We hypothesize that growth arrest combined with tissue polarity attenuates ROS as well as inappropriate MMP-3 activity and cytokines and that microenvironmental cues need to be considered in breast cancer therapy. Funded by the United States Department of Energy, Office of Biological and Environmental Research (DE-AC03 SF0098 to M.J.B.); an Innovator Award from the U.S. Department of Defense Breast Cancer Research Program (DAMD17-02-1-0438 to M.J.B.); the National Cancer Institute (CA64786 to M.J.B.); and DOD CA-BCRP fellowships to D.R. and J.F.