## 4 Discussion  
Insulin is an established mitogen known to promote breast cancer cell growth [10; 36]. The mitogenic actions of insulin in breast cancer cells are mediated by activation of IR. Earlier studies showed that IR was overexpressed in breast tumors when compared to normal breast tissue [10; 37]. In cancer cells, IR has been found to drive proliferative and mitogenic effects, which are distinct from the regular metabolic activity mediated by the receptor [5; 18]. Activation of IR phosphorylates IR substrate (IRS) which, in turn, activates multiple downstream signal transduction effectors such as phosphoinositide 3-kinase (PI3K)/AKT and ERK pathways [38; 39]. As a result, IR regulates several fundamental cellular processes such as cell proliferation, differentiation, cell cycle, and migration [17]. Insulin-like growth factor 1 receptor (IGF-1R) is a common dimerization partner of IR [5; 7]. IGF-1R/IR pathway mediated resistance to endocrine treatment and is further required for the growth of hormone-independent breast cancer [7; 38; 40]. A limited number of studies described the expression of IR in breast cancer tissues and its association with disease presentation and prognosis [41]. Results from this study demonstrated that high IR expression was significantly associated with low tumor grade and expression of hormone receptors, which are classified as favorable prognostic factors [42]. When stratified by menopausal status, these associations were found among premenopausal but not postmenopausal patients. Our findings showed no significant associations between IR expression with patient age, BMI, tumor size, or nodal status. In addition, our findings showed that patient survival was not affected by the IR expression status. In agreement with our findings, [PERSON] et al. found that high IR expression was significantly associated with low tumor grade, lymph node negativity, and positive expression of PR in a series of breast cancer patients who underwent surgical treatment at three University of Toronto hospitals [43]. High IR expression was associated with improved distant disease-free survival and OS among breast cancer patients compared to low expression status [43]. In addition, [PERSON] et al. described the expression of IR in a population-based cohort of 1,026 primary invasive breast cancer patients in Sweden [38]. Moderate-strong staining of IR was detected in 82% of breast cancer patients [38]. Strong IR expression was significantly associated with ER-positivity, while negative-weak expression of IR was associated with a triple-negative molecular status. However, IR expression lacked prognostic impact regarding event-free survival or distant metastasis among this cohort of Sweden breast cancer patients [38]. Alternatively, [PERSON] et al. examined the expression of IR in 159 specimens for Italian breast cancer patients and compared the expression to the content of 42 non-malignant breast tissues [10]. The expression of IR in breast cancer tissues was more than six-fold higher than  
Figure 3: Overall survival of breast cancer patients by expression status of IR (left panel) and c-MET (right panel). IR, insulin receptor. its expression in non-malignant breast tissue. In addition, [PERSON] et al. showed that IR expression was positively correlated with tumor size, histological grade, and ER content [10]. No correlations were found between IR levels and age, body weight, menopausal status, and nodal involvement of breast cancer patients [10]. [PERSON] et al. showed that mRNA levels of IR were significantly higher in cancer patients presented with advanced clinical stage of the disease compared to early stages [44]. As our findings demonstrate, a favorable prognostic impact for IR expression in breast cancer tissues and IR expression may be perceived as a marker of differentiation [43]. c-MET is a high-affinity receptor for HGF [45]. c-MET is classified as the prototype member of the RTK subfamily with Ron and Sea based on shared structural homology of c-MET [46].