The prognostic outcome of ‘type 2 diabetes mellitus and breast cancer’ association pivots on hypoxia-hyperglycemia axis

Abstract

Type 2 diabetes mellitus and breast cancer are complex, chronic, heterogeneous, and multi-factorial diseases; with common risk factors including but not limited to diet, obesity, and age. They also share mutually inclusive phenotypic features such as the metabolic deregulations resulting from hyperglycemia, hypoxic conditions and hormonal imbalances. Although, the association between diabetes and cancer has long been speculated; however, the exact molecular nature of this link remains to be fully elucidated. Both the diseases are leading causes of death worldwide and a causal relationship between the two if not addressed, may translate into a major global health concern. Previous studies have hypothesized hyperglycemia, hyperinsulinemia, hormonal imbalances and chronic inflammation, as some of the possible grounds for explaining how diabetes may lead to cancer initiation, yet further research still needs to be done to validate these proposed mechanisms. At the crux of this dilemma, hyperglycemia and hypoxia are two intimately related states involving an intricate level of crosstalk and hypoxia inducible factor 1, at the center of this, plays a key role in mediating an aggressive disease state, particularly in solid tumors such as breast cancer. Subsequently, elucidating the role of HIF1 in establishing the diabetes-breast cancer link on hypoxia-hyperglycemia axis may not only provide an insight into the molecular mechanisms underlying the association but also, illuminate on the prognostic outcome of the therapeutic targeting of HIF1 signaling in diabetic patients with breast cancer or vice versa. Hence, this review highlights the critical role of HIF1 signaling in patients with both T2DM and breast cancer, potentiates its significance as a prognostic marker in comorbid patients, and further discusses the potential prognostic outcome of targeting HIF1, subsequently establishing the pressing need for HIF1 molecular profiling-based patient selection leading to more effective therapeutic strategies emerging from personalized medicine.

The AGEs/RAGE Transduction Signaling Prompts IL-8/CXCR1/2-Mediated Interaction between Cancer-Associated Fibroblasts (CAFs) and Breast Cancer Cells

“…For instance, diabetes in premenopausal women has been correlated with a major risk of developing a breast tumor, mostly the aggressive subtype named triple-negative breast cancer (TNBC) [ 105 , 106 ]. In addition, previous studies have indicated that breast cancer mortality associated with distant metastasis is elevated in those patients with co-occurring low-grade chronic inflammatory conditions, such as obesity and T2DM [ 7 , 107 , 108 , 109 , 110 ]. Of note, the IL-8 serum levels were found markedly increased in the T2DM patients in relation to the healthy subjects, and positively correlated with worse metabolic control and an inflammatory state [ 111 ].…”

Recent Progress in the Diagnosis and Management of Type 2 Diabetes Mellitus in the Era of COVID-19 and Single Cell Multi-Omics Technologies

“…The association of T2DM and breast cancer was shown by the hypoxia-independent stabilization of HIF-1α via the insulin–PI3K–AKT, MAPK/ERK, IL-1, and NF-κB pathways. Subsequent HIF-1α-mediated events and the induction of glucose transporter GLUT1, glycogen synthase kinase, E-cadherin, and matrix metalloproteinases lead to epithelial–mesenchymal transition, the “entrance-hall” of cancer [ 133 ]. The risks and factors involved in cancer development in T2DM patients have been recently reviewed elsewhere [ 127 , 134 ].…”

Untitled

“…According to the recent studies, type two diabetes is a distinct risk factor for the progression of different cancers [8,9]. In addition, cancers that are related to one type of diabetes may not be linked to the other, such as breast cancer, which is mainly linked to type 2 diabetes and not type 1 diabetes [10]. The most common type of malignancy in women is breast cancer (23 percent of all malignancies) [11], and it ranks second overall when both sexes are taken into account [12].…”