**4.2 Activation of the Ras signaling pathway**

Activation of the Ras signaling pathway is commonly observed in mammary tumor progression. Adapter proteins such as Shc and Grb2 create some specific complexes with activated forms of Neu and PyV mT. The co-operation of Grb2 and Shc with these activated oncoproteins will result in stimulation of Ras signaling. In contrast to PyV mT, which signals to Ras only through its association with Shc, Neu can activate Ras through Grb2, Shc

Breast Cancer from Molecular Point of View: Pathogenesis and Biomarkers 109

Cdc25b make mammary glands hyperplasic and more sensitive to carcinogenic chemicals, it does not directly induce tumorigeneses. Recently, inhibitor of nuclear factor kappa-B kinase (IKK a, a responsible kinase for activation of NF-k B, was identified as a necessary factor for Cyclin D1-associated epithelial proliferation in MMTV-Neu (but not in MMTV- Ra s) mice

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

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,

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

Transforming growth factor-ß **(TGF- ß)** is a secreted cytokine which induces s growth arrest in normal epithelium. It interacts with the TGF- ß type II receptor (T ß RII) which followed by recruitment and phosphorylation of TGF- ß type I receptor (Tß RI) and activation of downstream signaling cascade. The cytostatic effect of TGF- ß is also seen on early tumor progression and is mediated through the regulation of both apoptosis and cell proliferation. However, TGF-ß signaling increases lung metastasis in some transgenic mouse models. Breast carcinomas are well known for overexpressed TG F- ß. Induct ion of TGF- ß 1 after tumor initiation do not exert much effect on proliferation of tumor, but remarkably increase the lung metastasis. These data support the hypothesis that that TGF -ß 1 may no longer

Another important tumor suppressor associated with mammary tumor development is p53. p53 is well-known for its involvement in a variety of cancer types. P53 gene is one of the most altered tumor suppressor genes in human breast cancer, such that around 50% of all

It has been reported that Insulin-like Growth Factor (IGF) may have effect in breast cancer progression. It has been showed that Retinoic Acid (RA) mediate their inhibitory effects on cell growth of cancerous human breast cancer cells "MCF7" via selective reduction of Insulin Receptor Subtype-1 (IRS-1) and its activity which results in the selective downregulation of IP3-kinase/AKT. High levels of Irs-1 in human breast tumors correlate with elevated incidence of disease recurrence. Although the insulin receptor substrates (IRS) were primarily identified, as the name implied, as a substrate for the insulin receptor (IR), Nowadays it has been known that these adapter proteins, are involved in activation of downstream pathways of several growth factor receptors such as insulin-like growth factor-1 receptor (IGF-1R), vascular endothelial growth factor receptor (VEGF-R), cytokine

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

MMP3,MMP7 and MMP9 have been established (21,22).

**5.2 Mutations in tumor suppressor genes** 

perform an inhibitory role in established tumors (24).

breast cancers include mutated form of p53 gene (25).

in plasminogen-deficient mice as well as in uPa-deficient mice (11,23).

attracted much attention (19,20)

(11).

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

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. (www.cellsignal.com).]
