**5.1 The role of extracellular matrix (ECM) enzymes**

108 Breast Cancer – Focusing Tumor Microenvironment, Stem Cells and Metastasis

and several other unidentified adapter proteins. Resultant phenomenon of Ras activation will be the recruiting of a number of downstream effector molecules including PI-3K, Raf serine kinase, GRB associated-binding protein (GAP) and Ras-related protein (Ral) (16).

Fig. 1. MAPKs cascades Mitogen-activated protein kinases (MAPK) are a family of Ser/Thr protein kinases widely conserved among eukaryotes and are involved in many cellular programs such as cell proliferation, cell differentiation, cell movement, and cell death. MAPK signaling cascades are organized hierarchically into three-tiered modules. MAPKs are phosphorylated and activated by MAPK-kinases (MAPKKs), which in turn are phosphorylated and activated by MAPKK-kinases (MAPKKKs). The MAPKKKs are in turn activated by interaction with the family of small GTPases and/or other protein kinases, connecting the MAPK module to cell surface receptors or external stimuli. [Source: Pathway diagram reproduced courtesy of Cell Signaling Technology, Inc.

Dysregulation of cell cycle can also results in malignant cell proliferation and Tumorigenesis. Cyclin D1, for example, has been reported to be overexpressed in human breast cancer (18). Observation has been confirmed in MMTV-Ras and MMTV-Neu mice deficit in Cyclin D1. Tumor development completely stops in these animals which show the critical role of Cyclin D1 in Ras-Neu transformation pathway..Although overexpression of

(www.cellsignal.com).]

**5. Dysregulation of cell cycle** 

Figure 1 presents an overview of Ras/MAPKs signaling pathway.

In addition to integrin family, which has discussed above, the role of other extracellular matrix (ECM) enzymes such as cathepsins and plasmin in tumorigensis and metastasis has attracted much attention (19,20)

Matrix metalloproteinases (MMP) are a family of matrix degrading enzymes associated with tumor progression, metastasis, and poor prognosis. A tumor cell must degrade the surrounding stroma to reach blood vessels. That's why it is thought that these degrading enzymes control the primary step in invasion and metastasis. The roles ofMMP2, MMP3,MMP7 and MMP9 have been established (21,22).

urokinase-type plasminogen activator (uPa ) is another extracellular degrading enzyme which cleaves plasminogen into plasmin. The latter can degrade ECM directly or indirectly via activating MMPs. PyV MT -associated lung metastasis shows remarkable decrease was in plasminogen-deficient mice as well as in uPa-deficient mice (11,23).
