**8. Metastasis suppressor genes**

### **8.1 E-cadherin**

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

chemotherapeutic agents. Proteins with direct interactions with MTDH/AEG1 are shown in green. Dotted line indicates pathways yet to be fully validated or characterized. [Source:

Fig. 5. Role of Stat3 signaling pathway to cancer metastasis. Activatin of STAT3 happens by recruitment to phosphotyrosine motifs within complexes of growth factor receptors (e.g., epidermal growth factor receptor), cytokine receptors (e.g., IL-6 receptor), or non-receptor

phosphorylated on a tyrosine residue by activated tyrosine kinases in receptor complexes. Phosphorylated Stat3 forms homodimers and heterodimers and translocates to the nucleus. In the nucleus, Stat3 dimers bind to specific promoter elements of target genes and regulate gene expression. The Stat3 signaling pathway regulates cancer metastasis by regulating the expression of genes that are critical to cell survival, cell proliferation, invasion, angiogenesis,

tyrosine kinases (e.g., Src and BCR-ABL) through their SH2 domain. Stat3 is then

and tumor immune evasion.

Figure 1 from Ref. 40] With permission

*E-cadherin* (a member of the cadherin superfamily of Ca2+-dependent adhesion cell surface molecules, expressed predominantly in epithelial tissues) has been demonstrated to correlates negatively with the potential of tumor invasion. Reduction and/or loss of Ecadherin expression in carcinomas will result in increased tumor metastasis because of the reduction in tumor cell adhesiveness and increased cell motility (49)

Tissue Inhibitors of Metalloproteinases

Breast Cancer from Molecular Point of View: Pathogenesis and Biomarkers 119

Profiling of metastamirs in human breast cancer has been resulted in to find the new molecular mechanisms in metastatic process. Significant increase in expression of some of miRNAs has been identified in breast tumors and some others have shown some correlation with biopathological features such as Her2, ER and PR status, tumor stage, and response to treatments. The most important miRNAs involved in different steps of developing breast tumor are miR-335, miR-17/20, and miR-146 (involved inmicroenvironment modification), let-7, miR-200 and miR-30 (BCSC phenotype formation); miR-21,miR- 12 6, miR-373, and miR-520 (local invasion), miR-7, miR-661 and miR-17/20 (survival in vasculature ) and miR-

Chemoresistance is also affected by miRNAs. Some miRNAs which play some roles in this step are miR-125b, miR-21, and miR -128. The mechanisms underlying miRNAs dysregulation in breast cancer development, whether dysregulated miRNA is a cause or consequence of pathological and many other questions remain to be explored (55). Some of

**miRNA involved Protein inhibited Function influenced** 

**miR-7** EGFR Anoikis resistance

**miR-30** Ubc 9 Anoikis resistance

**miR-520** CD 44 Local invasion

**miR-373** CD 44 Local invasion

**miR-21** Bcl-2 Colonization

**miR-145** IRS-1 Colonization

**miR-17/20** Cyclin D1 Colonization

**MiR-205** VEGF Angiogenesis

**MiR-9** E-cadherin Angiogenesis

Identifying biomarkers in early stages of breast cancer as helpful instruments for increasing breast cancer survival has opened an important window in researches. Immunohistochemical testing of tumor samples for estrogen receptor(ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER 2) is a common method which is widely used (56,57). Biomarkers in biological fluids are more useful because they don't need biopsy and invasive methods. Four metabolic biomarkers including Homovanillate, 4-hydroxyphenylacetate, 5-hydroxyindoleacetate and urea have been shown to be different in urine samples of cancer subjects, compared to control group (58). The

200 and let-7 (proliferation at distant sites).

Table 1. miRNAs and their function in cancer

**9. Biomarkers** 

the most important miRNAs have been mentioned in table 1.

The role of metalloproteinases (TIMPs) is inhibiting the activity of matrix proteinases (MMPs). As a result, they suppress tumor metastasis. An interesting paradox is that increased TIMPs are associated with progression to metastatic disease in some studies. One proposed explanation is that the balance between MMPs and TIMPs is important than the expression of each protein (50).
