Tumor-linked HER2 expression: association with obesity and lipid-related microenvironment

Abstract

Abstract:Obesity is associated with the risk of several health disorders including certain cancers. Among obesity-related cancers, postmenopausal breast carcinoma is a well-studied one. Apart from an increase in certain types of lipids in obesity, excess adipose tissue releases many hormone-like cytokines/adipokines, which are usually pro-inflammatory in nature. Leptin is one of such adipokines and significantly linked with the intracellular signaling pathways of other growth factors such as insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF), human epidermal growth factor receptor 2 (HER2). In general, HER2 is overexpressed in roughly 30% of breast carcinomas; its presence indicates aggressive tumor behavior. Conversely, HER2 has certain effects in normal conditions such as differentiation of preadipocytes, cardiovascular health and vitamin D metabolism. HER2 has no known endogenous ligand, but it may form dimers with other three members of the epidermal growth factor receptor (EGFR) family and can activate downstream signaling pathways. Furthermore, HER2 is intimately connected with several enzymes, e.g. fatty acid synthase (FASN), phosphatidylinositol 3-kinase (PI3K), AKT and mechanistic target of rapamycin (mTOR), all of which play significant regulatory roles in lipogenic pathways or lipid metabolism. In obesity-related carcinogenesis, characteristics like insulin resistance and elevated IGF-1 are commonly observed. Both IGF-1 and leptin can modulate EGFR and HER2 signaling pathways. Although clinical studies have shown mixed results, the behavior of HER2+ tumor cells including HER2 levels can be altered by several factors such as obesity, leptin and fatty acids. A precise knowledge is useful in new therapeutic approaches against HER+ tumors.

Association between serum HER2/ErbB2 levels and coronary artery disease: a case–control study

“…Similarly, in our multivariate linear regression analysis, we observed an independent association of BMI, LDL-C and triglycerides with HER2 levels, suggesting a close relation of HER2 with metabolism. Indeed, emerging evidences show that HER2 signaling is associated with obesity and the lipid-related microenvironment, and plays an important role in adipose differentiation [6,37]. Intriguingly, our study found an interaction between HER2 levels and BMI on the presence of CAD, indicating that HER2 signaling may significantly contribute to the progress of atherosclerosis when coupled with other factors, such as obesity.…”

“…Intriguingly, our study found an interaction between HER2 levels and BMI on the presence of CAD, indicating that HER2 signaling may significantly contribute to the progress of atherosclerosis when coupled with other factors, such as obesity. Experimental studies found that the molecules governing lipid metabolism can significantly interact with HER2 signaling, which alters the behavior of various cell types in multiple pathological conditions [6]. For instance, leptin, an important proinflammatory adipokine, has been found to cause vascular dysfunction by increasing HER2 activity in the arterial wall [13].…”

“…Although important to homeostasis, abnormal regulation or production of HER2 can promote diseases [2,3]. Intriguingly, clinical evidences have recently associated HER2 activity with glucose and lipid metabolism [6][7][8][9]. Circulating HER2 levels are found to be positively correlated with the parameters of obesity and insulin resistance [7,8], and increased circulating HER2 levels are associated with a higher risk of developing diabetes [9].…”

The influence of leptin on the process of carcinogenesis

“…Incorrect control of the cancer cells’ proliferation processes is, among others, caused by HER2 receptor transactivation (human epidermal growth factor receptor 2) [11]. HER2 is overexpressed in about 30% of breast cancer cases, and its presence indicates a more aggressive course of the disease (a negative prognosis factor) [17]. The influence of leptin on an increased proliferative activity of the breast cancer cells is also observed as a result of activation of the JAK/STAT3 and PI3K/AKT pathways [11, 16].…”

IGF-1 Interacted With Obesity in Prognosis Prediction in HER2-Positive Breast Cancer Patients

“…was leptin, a cytokine secreted mainly by adipoctyes and closely related to body weight and body fat (37). Leptin could induce a 2 to 3-fold increase in liver or muscle-derived IGF-1 in aged calorie-restricted rodent model (38).…”