biomolecules Review Insulin/IGF Axis in Breast Cancer: Clinical Evidence and Translational Insights Federica Biello 1,* , Francesca Platini 2, Francesca D’Avanzo 2, Carlo Cattrini 2 , Alessia Mennitto 2, Silvia Genestroni 2, Veronica Martini 2,3, Paolo Marzullo 1,4 , Gianluca Aimaretti 1 and Alessandra Gennari 1 1 Department of Translational Medicine, University of Eastern Piedmont, Via Solaroli 17, 28100 Novara, Italy; [email protected] (P.M.); [email protected] (G.A.); [email protected] (A.G.) 2 Division of Oncology, University Hospital “Maggiore della Carità”, 28100 Novara, Italy; [email protected] (F.P.); [email protected] (F.D.); [email protected] (C.C.); [email protected] (A.M.); [email protected] (S.G.); [email protected] (V.M.) 3 Lab of Immuno-Oncology, CAAD, Center of Autoimmune and Allergic Disease, University of Eastern Piedmont, 28100 Novara, Italy 4 Division of General Medicine, IRCCS Istituto Auxologico Italiano, Ospedale S. Giuseppe, 28921 Piancavallo-Verbania, Italy * Correspondence: [email protected] 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, Citation: Biello, F.; Platini, F.; its capacity for lowering circulating insulin levels with indirect endocrine effects that may impact D’Avanzo, F.; Cattrini, C.; Mennitto, on tumor cell proliferation; second, its direct influence on many pro-cancer signaling pathways that A.; Genestroni, S.; Martini, V.; are key drivers of BC aggressiveness. Methods: In the present review, the interaction between BC, Marzullo, P.; Aimaretti, G.; Gennari, host metabolism, and patients’ prognosis has been reviewed across available literature evidence. A. Insulin/IGF Axis in Breast Cancer: Conclusions: Obesity, metabolic syndrome, and insulin resistance are all involved in BC growth Clinical Evidence and Translational and could have a relevant impact on prognosis. All these factors act through a pro-inflammatory Insights. Biomolecules 2021, 11, 125. state, mediated by cytokines originated in fat tissue, and seem to be related to a higher risk of BC https://doi.org/10.3390/biom11010125 development and worse prognosis. Received: 29 December 2020 Keywords: breast cancer; host metabolism; insulin resistance; IGF; BMI Accepted: 18 January 2021 Published: 19 January 2021 Publisher’s Note: MDPI stays neutral 1. Introduction with regard to jurisdictional claims in published maps and institutional affil- In Western Countries, a large proportion of diseases, including cancer, can be at- iations. tributed to a Western lifestyle, in association with physical inactivity and metabolic impair- ment. A growing body of evidence suggests a strong relationship among type 2 diabetes mellitus (T2DM), insulin, obesity, and cancer. The association between insulin and cancer is based on the strong anabolic effect of hyperinsulinemia that leads to proliferative tissue abnormalities, stimulation of DNA synthesis, and cell proliferation [1]. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. Preclinical studies demonstrated that insulin can promote tumorigenesis through This article is an open access article a direct effect on epithelial tissues or indirectly by affecting the levels of other modula- distributed under the terms and tors, such as the insulin-like growth factor (IGF) family of receptors, sex hormones, and conditions of the Creative Commons adipokines [2]. IGFs are endocrine mediators of growth hormones that act in a paracrine Attribution (CC BY) license (https:// and autocrine fashion to regulate cell growth, differentiation, apoptosis, and transformation creativecommons.org/licenses/by/ in different tissues, including breast tissue. Insulin receptors (IR) regulate glucose, protein, 4.0/). and lipid metabolism through the phosphatidylinositol 3-kinase (PI3K)/AKT pathway and Biomolecules 2021, 11, 125. https://doi.org/10.3390/biom11010125 https://www.mdpi.com/journal/biomolecules Biomolecules 2021, 11, 125 2 of 11 through the activation of the RAS/RAF/MAPK kinase/ERK cascade that is involved in cell proliferation, survival, and migration [3]. Breast cancer (BC) is the most common cancer in women, with over 2 million of new diagnosis/year in 2018 in the world [4]. In the last years, the possible interactive role of host metabolism and BC has risen in importance, and many clinical and preclinical studies have been developed to understand their possible correlations. In particular, obesity has been consistently reported as a risk factor for different BC subtypes, including triple negative (TNBC) and luminal BC [5,6]. Available evidence also shows that BC cells have significantly higher insulin receptor (IR) levels than normal breast cells [7], suggesting that this signaling pathway may play a role in BC development and progression, and may become a potential therapeutic target. Furthermore, epidemiologic studies have shown that high levels of plasmatic IGF are correlated with an increased risk of several cancers, including breast, and that IGF-2 signaling is possibly associated with cancer progression [8]; it is also known that the loss of tumor suppressor genes such as BRCA1, p53, and PTEN leads to an increase in IGF-1R expression in tumors [9]. In this preclinical context, E-cadherin is a putative regulator of IGF1 signaling; the loss of E-cadherin expression can directly increase IGF1-R pathway activation in many BCs. The oncogenic signaling network may be influenced by the regulation of IGF1-R by E-cadherin, particularly because E-cadherin itself is involved in mechanisms of escape of tumor cells and metastasization. In addition, the transcription of E-cadherin is repressed or genetically lost in subset of breast tumors, such as invasive lobular breast carcinoma (ILC), in which its loss of functional occurs in about 95%. Due to the loss of E-cadherin protein, ILC cells grow in linear patterns throughout the breast tissue, lacking the ability to form adhesion junctions, in contrast to the solid mass growth of the most frequent subtype of breast cancer, invasive ductal breast carcinoma (IDC) [10,11]. In BC patients, the possible role of the IGF pathway in resistance to cancer therapy has been investigated, although the exact mechanism is not completely clear. In partic- ular, the IGF pathway seems to be involved in modulating the expression of Epidermal Growth Factor receptors (EGFR) in cancer cells, and, as a consequence, it might have a key role in inducing resistance to endocrine therapies in estrogen receptor (ER)-positive BC patients [12,13]; in addition, direct interactions between the IGF-1R and the HER2 pathway have been reported and may contribute to the resistance to anti-HER2–targeted therapy [14] (Table1). Table 1. Insulin-like growth factor (IGF) expression (%) according to breast cancer (BC) patients’ characteristics: A higher expression is observed in patients with worse prognostic features. BC Characteristics IGF Expression (%) Histological subtype ER+ 60 TNBC 20 Tumor staging T1-T2 35 T3-T4 65 Lymph nodes metastasis Yes 60 No 40 ER: Estrogen receptor; TNBC: Triple-negative breast cancer. Adapted from [15,16]. 2. Host Metabolism and Breast Cancer Risk The possible relationship between cancer and obesity is very complex: Body mass index (BMI), an easy and immediate biometric index, deriving from weight and height and routinely used in clinical practice, cannot be considered an exact index of metabolic health, as obese patients can be metabolically healthy and normal-weight patients can be un-healthy. Moreover, its role as a risk factor for BC is dual: recent evidence has shown that Biomolecules 2021, 11, 125 3 of 11 increased adiposity in childhood and in early adulthood is associated with a reduced risk of BC, whereas increased adiposity after menopause is associated with an increased BC risk [17]. A large pooled analysis on about 750,000 premenopausal women demonstrated a higher risk of BC in those who were underweight as compared to those obese, showing an inverse association between BMI and BC risk, suggesting a critical correlation between young adulthood adiposity and cancer; this association seems to be independent from other well-known BC risk factors. The association between BMI and hormone receptor positive BC is stronger in young adulthood, but not consistent in later ages, while the correlation between obesity and TNBC is more controversial. The association between estrogen receptor-positive (ER+) BC and obesity identifies a possible hormonal role in tumorigenesis, as the adipose tissue is the principal site of estrogen release in childhood; for this reason, overweight in childhood seems to induce early breast differentiation and to increase expression of tumor suppression gene [18]. The relationship between BC subgroups and obesity has been investigated in an Italian trial on 2148 women. Overweight/obese women had significantly larger tumors