Influence of Type 2 Diabetes and Adipose Tissue Dysfunction on Breast Cancer and Potential Benefits from Nutraceuticals Inducible in Microalgae

Abstract

Breast cancer (BC) represents the most prevalent cancer in women at any age after puberty. From a pathogenetic prospective, despite a wide array of risk factors being identified thus far, poor metabolic health is emerging as a putative risk factor for BC. In particular, type 2 diabetes mellitus (T2DM) provides a perfect example bridging the gap between poor metabolic health and BC risk. Indeed, T2DM is preceded by a status of hyperinsulinemia and is characterised by hyperglycaemia, with both factors representing potential contributors to BC onset and progression. Additionally, the aberrant secretome of the dysfunctional, hypertrophic adipocytes, typical of obesity, characterised by pro-inflammatory mediators, is a shared pathogenetic factor between T2DM and BC. In this review, we provide an overview on the effects of hyperglycaemia and hyperinsulinemia, hallmarks of type 2 diabetes mellitus, on breast cancer risk, progression, treatment and prognosis. Furthermore, we dissect the role of the adipose-tissue-secreted adipokines as additional players in the pathogenesis of BC. Finally, we focus on microalgae as a novel superfood and a source of nutraceuticals able to mitigate BC risk by improving metabolic health and targeting cellular pathways, which are disrupted in the context of T2DM and obesity.

Keywords: adipokines; breast cancer; insulin resistance; microalgae; nutraceuticals; type 2 diabetes mellitus.

Figure 1

The impact of type 2 diabetes mellitus (T2DM) and hypertrophic, dysfunctional adipose tissue on breast cancer (BC) pathogenesis. The hallmarks of T2DM, namely hyperglycaemia and hyperinsulinemia, and the altered secretome of dysfunctional, hypertrophic adipocytes promote BC development and aggressiveness.

Figure 2

Microalgae-derived nutrients as tool to mitigate the impact of type 2 diabetes mellitus (T2DM) on breast cancer (BC). The microenvironment typical of T2DM and prediabetes, characterised by hyperglycaemia and hyperinsulinemia, promotes the activation of anabolic pathways. Insulin, upon binding to its receptor, triggers the activation of the AKT-mTOR axis, which enhances BC cell growth and proliferation. Furthermore, hyperinsulinemia triggers also the activation of the insulin mitogenic pathway, which leads to the nuclear translocation of ERK, leading to the upregulation of pro-survival and proliferation genes. Not only hyperinsulinemia but also IGF-1 activates the signalling cascade, which leads to the nuclear translocation of ERK. Furthermore, IGF-1 promotes the activation of the JAK/STAT3 pathway involved in epithelial to mesenchymal transition (EMT), BC growth, invasiveness, migration and metastasis promotion. The activation of TLR and interleukin receptors (reported in the figure only as IL-1R) culminates with the activation of the JAK/STAT3 pathway and the nuclear translocation of NF-kB via the MYD88/IRAK1-4/TRAF6/TAK1/IkB cascade, which promotes EMT and acts as a pro-survival stimulus in BC [137]. Nutrients, naturally present or inducible in response to environmental stressors in microalgae approved for human consumption, are able to counteract the aforementioned malignant pathways, promoted by T2DM and dysfunctional adipose tissue secretome, in BC cells. AKT, protein kinase B; ERK, extracellular signal-regulated-kinase; IGF-1, insulin-like growth factor-1; IGF-1R, insulin-like growth factor-1 receptor; IkB, NF-kappa-B inhibitor; INSR, insulin receptor; IRAK, interleukin 1 receptor-associated kinase 1-4; JAK, Janus kinase; MEK, mitogen-activated protein kinase kinase; mTOR, mechanistic target of rapamycin complex; MYD88, myeloid differentiation primary response protein 88; NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; PPAR-α/γ, peroxisome proliferator-activated receptors α/γ; PUFAs, polyunsaturated fatty acids; RAF, rapidly accelerated fibrosarcoma; RAS, rat sarcoma; STAT3, signal transducer and activator of transcription 3; TAK, transforming growth factor-β-activated kinase; TLR, toll-like receptor; TRAF, TNF receptor-associated factor.