## 1 Introduction  
Receptor tyrosine kinases (RTKs) are transmembrane receptors known to bind growth factors mediating the integration and interpretation of diverse extracellular stimuli and functions [1]. Historically, RTKs define the prototypical class of oncogenes involved in most forms of human malignancies [2]. Deregulations of RTKs in terms of mutations or aberrant expression enhance cancer cell proliferation, survival, and invasion, which ultimately drive the development of aggressive tumor phenotypes [3]. The growth of breast cancer cells is under coordinate regulation of growth factors and hormones acting through their respective receptors [1; 4]. Multiple RTKs were identified for their oncogenic potential in breast cancer. Insulin receptor (IR) is an RTK increasingly recognized to be involved in cancer development and progression [5]. Accumulating evidence revealed a role for insulin and insulin-like growth factors in development and progression of breast cancer [6; 7; 8]. Overexpression of IR was reported in human breast cancer tissues [7; 9; 10; 11]. In a mouse model of type II diabetes, IR promoted breast cancer mitogenesis and hyperinsulinemia accelerated the progression of mammary tumors [12]. Insulin resistance and hyperinsulinemia have been shown to drive mitogenic tumor growth and increase cell proliferation and migration through activation of IR signaling [5; 13; 14; 15]. In line with this, conditions associated with insulin resistance such as type II diabetes mellitus, obesity, and metabolic syndrome are now recognized as important risk factors for the development and progression of a variety of malignancies including breast cancer [5; 13; 16]. Aberrant IR expression has been shown to mediate cancer resistance to both conventional and targeted therapies [17]. Measures to improve insulin resistance and obesity reduce the risk of epithelial cancers. Metformin reduced breast cancer risks by reducing insulin levels [11]. In addition, metformin treatment in breast cancer patients who were not diabetic reduced levels of IR expression in tumors and reduced phosphorylation of several downstream signaling molecules such as protein kinase B (AKT), extracellular signal-regulated kinase 1/2 (ERK1/2), and AMP-activated protein kinase (AMPK) [18]. Despite the availability of strong evidence from preclinical studies to support the oncogenic potential of IR in breast cancer cells, the impact of IR expression on the clinicopathologic characteristics of breast cancer patients is less clear. The hepatocyte growth factor (HGF) receptor, c-MET, is an RTK known to promote oncogenic transformation and progression of cancers. Activation of c-MET by its natural ligand, HGF, is associated with aggressive tumor growth characterized by cancer cell proliferation, migration, invasion, angiogenesis, and metastasis [19; 20]. Clinical studies showed that c-MET is overexpressed in 20%-30% of breast cancer cases and is a strong, independent predictor of reduced survival and poor outcomes [21; 22]. c-MET expression in breast tissue is variable with the lowest levels in normal breast tissue, higher expression in ductal carcinoma in situ (DCIS), and the highest levels in invasive carcinoma [23]. Despite its oncogenic potential, the impact of c-MET expression on established prognostic factors in breast cancer patients is less established. In addition, most studies evaluated the expression of c-MET in basal-like tumors and little data is available regarding the expression of c-MET in other molecular subtypes. c-MET has been shown to be necessary for an optimal response to insulin in hepatocytes by engaging with IR in a hybrid complex of both receptors [24]. Previous reports had addressed expression of IR and c-MET in breast cancer tissue. However, less data is available on the association between expression levels of these receptors in breast cancer patients. In addition, the impact of IR and c-MET expression on disease prognosis and clinicopathologic characteristics is inconsistent.