A Molecular Link Between Diabetes and Breast Cancer: Therapeutic Potential of Repurposing Incretin-based Therapies for Breast Cancer

Abstract

: Female breast cancer recently surpassed lung cancer and became the most commonly diagnosed cancer worldwide. As per the recent data from WHO, breast cancer accounts for one out of every 8 cancer cases diagnosed among an estimated 2.3 million new cancer cases. Breast cancer is the most prevailing cancer type among women causing the highest number of cancer-related mortality. It has been estimated that in 2020, 68,5000 women died due to this disease. Breast cancers have varying degrees of molecular heterogeneity; therefore, they are divided into various molecular clinical sub types. Recent reports suggest that type 2 diabetes (one of the common chronic diseases worldwide) is linked to the higher incidence, accelerated progression, and aggressiveness of different cancers; especially breast cancer. Breast cancer is hormone-dependent in nature and has a cross-talk with metabolism. A number of antidiabetic therapies are known to exert beneficial effects on various types of cancers, including breast cancer. However, only a few reports are available on the role of incretin-based antidiabetic therapies in cancer as a whole and in breast cancer in particular. The present review sheds light on the potential of incretin based therapies on breast cancer and explores the plausible underlying mechanisms. Additionally, we have also discussed the sub types of breast cancer as well as the intricate relationship between diabetes and breast cancer.

Anti-cancer effects of sitagliptin, vildagliptin, and exendin-4 on triple-negative breast cancer cells via mitochondrial modulation

“…Recently, we have comprehensively reviewed the crosstalk between diabetes and breast cancer pathways and highlighted the importance of the repurposing of incretinbased antidiabetic therapies in breast cancer (Parmar et al, 2021;Parmar et al, 2022;Jaiswal et al, 2022).…”

“…Glucagon-like peptide-1 (GLP-1) is an incretin, which is formed by the posttranslational processing of proglucagon gene transcript in intestinal L-cells of the gastrointestinal tract (GIT) and exerts glucose-lowering effects via binding with GLP-1 receptors. Incretins exert pleiotropic antidiabetic effects, including insulin secretion in response to glucose, diminished glucagon secretion, delayed gastric emptying, reduced hepatic glucose output, and increased pancreatic β-cell survival (Jaiswal et al, 2022). However, the metabolic fate of GLP-1 is determined by an enzyme known as dipeptidyl peptidase-IV (DPP-IV), which is a subset of oligopeptidase encoded by CD26.…”

“…Therefore, it inactivates the incretin and promotes diabetes. Interestingly, incretin-based antidiabetic therapies, including GLP-1 agonists and DPP-IV inhibitors, are known to exert pancreatic as well as extra pancreatic effects; some of these pathways have indicated their potential in the treatment of breast cancer (Jaiswal et al, 2022).…”

“…In our recent review on the therapeutic potential of repurposing the incretin-based therapies in breast cancer, we explored all the plausible molecular mechanism(s) of DPP-IV inhibitors and GLP-1 agonists along with the cancerpromoting role of DPP-IV (Jaiswal et al, 2022). Recently, we also reported the anti-cancer role of AMPK activator, 5aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) via increased expression of mitochondrial biogenesis related genes PGC-1α, NRF-1, NRF-2, and TFAM (Tripathi et al, 2022) which is in line with the reports available on the AMPK activation by sitagliptin, vildagliptin and exendin-4 (Zheng et al, 2018;Nath et al, 2021;Li et al, 2021).…”

Restructuring the ONYX-015 adenovirus by using spike protein genes from SARS-CoV-2 and MERS-CoV: Possible implications in breast cancer treatment

“…Breast cancer (BC) is the second leading cause of cancer-related mortality and the most common malignancy among women [1] . Most of the BC subtypes are being associated with mutations in BRCA1 and BRCA2; however, p53 mutations are associated with more aggressive disease outcomes and poor prognosis [2] .…”