Insulin/IGF Axis in Breast Cancer: Clinical Evidence and Translational Insights

Abstract

Background: Breast cancer (BC) is the most common neoplasm in women. Many clinical and preclinical studies investigated the possible relationship between host metabolism and BC. Significant differences among BC subtypes have been reported for glucose metabolism. Insulin can promote tumorigenesis through a direct effect on epithelial tissues or indirectly by affecting the levels of other modulators, such as the insulin-like growth factor (IGF) family of receptors, sex hormones, and adipokines. The potential anti-cancer activity of metformin is based on two principal effects: first, its capacity for lowering circulating insulin levels with indirect endocrine effects that may impact on tumor cell proliferation; second, its direct influence on many pro-cancer signaling pathways that are key drivers of BC aggressiveness. Methods: In the present review, the interaction between BC, host metabolism, and patients’ prognosis has been reviewed across available literature evidence. Conclusions: Obesity, metabolic syndrome, and insulin resistance are all involved in BC growth and could have a relevant impact on prognosis. All these factors act through a pro-inflammatory state, mediated by cytokines originated in fat tissue, and seem to be related to a higher risk of BC development and worse prognosis.

Circular RNA: A promising new star for the diagnosis and treatment of colorectal cancer

“…Among them, the insulin-like growth factor (IGF) plays an important regulatory role in CRC and other malignant tumors, indicating that circRUNX1 can be used as a tumor promoter and is expected to become a potential drug treatment target for CRC. [105][106][107][108][109] In CRC, circPVT1 is upregulated and participates in the proliferation and metastasis of CRC. However, it is noteworthy that overexpression of miR-145 significantly reverses the effect of upregulated circPVT1 on the metastasis of CRC, suggesting that miR-145 is a key downstream effector of circPVT1-mediated CRC metastasis.…”

Metformin and Breast Cancer: Where Are We Now?

“…These pathways are commonly deregulated in tumor cells, thus providing a mechanistic link between insulin/IGF1 and cancer initiation and progression via enhanced cancer cellular motility and invasion, anaerobic metabolism, dysregulation of epithelial to mesenchymal transition (EMT), tissue inflammation, reactive oxygen species (ROS) production, and angiogenesis, among others [ 21 , 23 ]. Importantly, breast cancer cells express significantly higher IR and IGF1-R levels than normal breast tissues [ 5 , 10 ]. Insulin levels have been related to poor prognosis in breast cancer [ 24 ], and persistent hyperinsulinemia reduces levels of IGF Binding Protein 1 (IGFBP-1), thereby increasing the bioactive concentrations of IGF1 [ 25 ].…”

“…Insulin can promote tumorigenesis through a direct effect on epithelial tissues or indirectly by affecting the levels of other modulators, such as the insulin-like growth factor 1 (IGF1), hormones, and adipokines [ 5 , 8 ]. Moreover, some metabolic changes derived from insulin resistance have been involved in tumor development, aggressiveness, treatment response, and poorer prognosis [ 9 , 10 , 11 ].…”

Metabolomic Identification of Anticancer Metabolites of Australian Propolis and Proteomic Elucidation of Its Synergistic Mechanisms with Doxorubicin in the MCF7 Cells

“…As a result, cholesterol was not available as a substrate for estrogen production in ovarian cancer cells. The PON2-dependent downregulated expression of IGF-1 and suppressed estrogen production in the ovaries may also be beneficial for breast cancer treatment [176][177][178][179]. In addition, similar to the inhibition of ovarian tumours, the PON2mediated inhibition of breast cancer can be speculated as both cancers share common etiology with BRCA1 and BRCA2 mutations and elevated estrogen levels [180][181][182].…”