Obesity is one of the most important public health problems the world faces today. It is associated with the risk of a number of diseases such as type 2 diabetes, cardiovascular disorders and certain cancers including postmenopausal breast cancer, which is the best example of obesity-related tumor development.
The inflammatory situation in obesity may create a state of insulin resistance where cells cannot utilize glucose appropriately due to the defective response to insulin. To overcome this condition, the pancreas produces more insulin, which causes hyperinsulinemia, alterations in IGF-binding proteins (IGFBPs), and increased biosynthesis of IGF-1 from the liver. Finally, in obesity several biological components such as elevated bioavailable IGF-1, pro-inflammatory adipokines like leptin, and angiogenic factors like VEGF play a key role in the pathogenesis of cancer.
In their review article published in Hormone Molecular Biology and Clinical Investigation, the authors present a detailed review on research carried out on the tumor-linked HER2 (human epidermal growth factor) expression and its association with obesity and lipid-related microenvironment.
Cancer cells utilize growth factors to progress tumors
For healthy proliferation and maintenance of different cells in our body, numerous growth factors and their receptors constantly function in harmony. Certain growth factors such as epidermal growth factor (EGF), insulin-like growth factor (IGF) and vascular endothelial growth factor (VEGF) have been well-studied in various scientific experiments. Nevertheless, after malignant transformation, usually cancer cells utilize these growth factors for tumor progression and metastasis.
The receptors for EGF and related growth factors constitute an important biological family, which is known as EGFR or erythroblastic leukemia viral oncogene homolog B (ErbB) or human epidermal growth factor receptor (HER) family. There are four members in this receptor family. Among these four members, EGFR and HER2 or neuro/glioblastoma derived oncogene homolog (neu) are commonly studied growth factor receptors in the field of cancer research.
Apart from EGF, several other biomolecules or ligands can bind to the EGFR and perform a wide range of functions. On the other hand, there is no ligand for HER2. However, HER2 is a constitutively active protein, which can participate with other family members to activate intracellular signaling pathways.
Overexpression of HER2 related to poor prognosis in breast cancer
Overall, HER2 has a number of physiological roles: this receptor is particularly helpful for the survival of heart muscle cells. In neoplastic condition, cancer cells possibly acquire the benefits of HER2. Accumulating evidence shows that many cancers overexpress HER2. In general, studies on breast cancer suggest that HER2 overexpression is associated with poor prognosis. Interestingly, HER2 expression and functions have been demonstrated to be modified by different obesity- and/or lipid-related components, e.g., hormone-like cytokine leptin, fatty acids, fat-soluble vitamins and fatty acid synthase enzyme.
Moreover, various EGFR/HER2-associated intracellular signaling molecules are also linked with signaling pathways of a number of obesity-related factors such as insulin-like growth factor–1 and leptin. Therefore, synergistic effects of different pathways could significantly alter tumor behavior.
More insight needed
Evidence suggests the various beneficial effects of HER2, including protection of the heart. Although HER2-targeted anti-cancer therapy (like trastuzumab) shows encouraging results, more insight is needed into the precise functions of HER2 in our physiological system. A better understanding is helpful in the development of new anti-HER2 therapeutic approaches.