## 4 Discussion
HGF binding induces c-MET dimerization and subsequent activation of several downstream transducers and adaptors including PI3K, Src, Grb2, Shc, and signal transducer and activator of transcription (STATs) [45]. Dysregulation of c-MET signaling upregulates diverse tumor cell functions including cell proliferation, survival, cell scattering and motility, epithelial-to-mesenchymal transition, angiogenesis, invasion, and metastasis [47]. In addition, high c-MET expression is critical for acquiring resistance toward chemotherapy and targeted therapies [48; 49]. Findings from this study revealed that c-MET is strongly expressed in breast cancer tissues and its levels are associated with hormone-receptor expression and luminal subtype among premenopausal breast cancer patients. However, no associations were found between c-MET expression and other tumor characteristics or patient survival in this analysis. In agreement with our results, several studies revealed a lack of association between c-MET expression and prognostic factors such as patient age, tumor size, and lymph node status [50]. [PERSON] et al. demonstrated a lack of correlation between c-MET expression and clinicopathological characteristics or prognosis among a cohort of patients diagnosed with triple-negative breast cancer [51]. [PERSON] et al. evaluated the expression of c-MET in 40 primary breast cancer patients with positive axillary lymph nodes in Germany and revealed a lack of association between receptor levels and age, lymph node involvement, ER, PR, tumor size, or grade [52]. [PERSON] et al. showed that c-MET immunoreactivity was associated with low histological grade and favorable prognostic and predictive factors such as ER and PR positivity and negative HER2 expression [53]. Nevertheless, c-MET expression was not significantly associated with other prognostic factors such as tumor size, lymph node status, and stage [53]. [PERSON] et al. showed that expression of c-MET in luminal tumors was associated with lymph node metastasis and reduced OS suggesting that c-MET expression could be utilized as a prognostic marker for risk stratification and treatment of patients with hormone receptor-positive breast cancer [54]. [PERSON] et al. also showed that increased c-MET expression in breast cancer tissues was associated with increased tumor size and stage, and reduced OS [48]. c-MET expression was significantly associated with the tumor grade in a series of patients diagnosed with triple-negative breast cancer from Greece and Austria [55]. Results from a meta-analysis of 6010 breast cancer cases indicated that c-MET overexpression correlated with poor relapse-free survival (RFS) and OS in Western patients. However, such an association was not observed among Asian patients [56]. Inconsistencies in findings correlating IR and c-MET expression with the clinicopathologic characteristics of breast cancer or the prognostic impact could be attributed to different approaches applied to assess immunostaining of target receptors and differences in populations examined. Our findings revealed that breast cancer tissues showed a significant positive correlation for the expression of IR and c-MET. A limited number of studies addressed the potential crosstalk between IR and c-MET. [PERSON] et al. reported that c-MET is essential for an optimal response to insulin in hepatocytes in which c-MET directly engage with IR in a hybrid complex of both receptors [24]. Though this finding has been shown in hepatic tissue, it is possible that IR and c-MET receptor hybrids are formed in cancerous tissues as well. This is particularly important since high expression of both receptors was found among luminal disease and, thus, mitogenic signaling in these tumors could be, in part, dependent on IR and c-MET RTKs, which could enable luminal tumors to escape the suppressive effects of endocrine treatments. Expression of IR and c-MET in breast cancer tissues could make them sensitive to inhibitors targeted for both receptors.