**4. Role of NF- κB**

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

kinase1 (IRAK1), TNF receptor associated factor (TRAF) 6, IKBKG which codes NF-kappa-B essential modulator (NEMO) protein and IKBKB which codes inhibitor of nuclear factor kappa-B kinase subunit beta (IKK-β) protein in NK- kB signaling pathway. PIK 3CA, the gene encoding the catalytic subunit of phosphatidylinositol 3-kinase (PI3K), is mutated in about 20 – 30% of breast tumors. TP53 mutations are found in about 30 – 35% of cases (10). Two newly identified genes, BRCA1 (Breast Cancer gene A1) and BRCA 2 (Breast Cancer gene A2), have been identied and categorized as human tumor suppressor genes. Mutations in these two genes have been found in the majority of hereditary breast cancer cases. Until the age of 70 women with mutated BRCA1 or BRCA2 genes faces to 45-85% increase in the risk of developing breast cancer. Several studies have demonstrated that patients with mutation in BRCA1 usually bear triple-negative kind breast tumors. In contrast, pathologic characteristics of BRCA2-mutant cases did not seem to be very different with non-carriers. Both these two genes play important roles in DNA repair in a common pathway. BRCA 1 is necessary for mammary stem cell differentiation, a function that could

Mutations usually result in dysregulation of signal transduction pathways. Increased expression of specific receptor tyrosine kinases (RTKs) has been implicated in the genesis of a significant proportion of sporadic human breast cancers. Increased activity of some of tyrosine kinases can result in aberrant cell proliferation. This phenomenon may result in cell transformation. For example, amplification and overexpression of neu/erbB2 protooncogene is observed in 20–30% human breast cancer, and is inversely correlated with the

The epidermal growth factor receptor (EGFR) family is a member of growth factor receptors which consists of four members: EGFR, ErbB2/Neu, ErbB 3, and ErbB 4. Increase ErbB2 expression, has been further associated with poor clinical outcome, is observed in 20 – 30% of sporadic breast tumors. The main reason is ErbB2 gene amplification (11). Increased level of tyrosine phosphorylated ErbB3 has been also reported. The important point is that ErbB3 is a bridge which links the phosphatidyl inositol-3 kinase (PI-3K) signaling molecule to Neu which has attracted much attention because of its potent transforming properties. This oncogene activates a number of common signaling pathways by providing specific binding sites for a variety of signaling molecules that include either Src Homology 2 (SH2) or phosphotyrosine binding/interacting domains. Co-expression of ErbB2 and ErbB3 RTKs is

 Mammary epithelial expression of Polyoma virus middle T (PyV mT) antigen, another tyrosine kinase involved in murine mammary tumorigenesis and metastasis, results in the rapid induction of multifocal metastatic mammary tumors. Since these tumors occur during early steps of mammary gland development and involve whole of the gland, expression of PyV mT will result in transformation of the primary mammary epithelium. This molecule is also associated with many signaling pathways via Src Homology 2 (SH2) or

It has been shown that Activated growth factor receptors can interact with integrin receptors and control their biological function in cancerous cells. An example is the stimulation of a6ß1 integrin through association with activated members of the EGFR family which conversely results in activation of EGFR family phosphorylation. Induction of tumor by the PyV M T oncogene is also dependent on the presence of functional ß1-integrin. Lack of functional ß1-integrin makes tumor cells unable to enter the cell cycle. Although, these

explain its tissue-specificity.

survival of the patient.

usually observed in common tumor progression (11,12).

phosphotyrosine binding/interacting domains (13).

Because of the wide range of activities of transcription factor NF- κB in apoptosis and cell survival and cell proliferation pathways as well as cell adhesion and angiogenesis it plays a remarkable role in tumorigeneses.

Regulatory influence of NF- κ B on the expression of various tumor-promoting molecules such as MMP, cycloxygenase 2, inducible nitric oxide synthase, chemokines, and inflammatory cytokines explain its significant effect on bearing cancer. NF- κB increased the expression of these molecules, all of which enhance tumoral cell invasion and angiogenesis. Other aspect of the role of NF- κB in tumorigeneses includes increasing expression of protooncogenes such as c- myc and cyclin D1 which directly stimulate proliferation. (14)
