Challenges and perspectives in the treatment of diabetes associated breast cancer

Abstract

Type 2 diabetes mellitus is one of the most common chronic disease worldwide and affects all cross-sections of the society including children, women, youth and adults. Scientific evidence has linked diabetes to higher incidence, accelerated progression and increased aggressiveness of different cancers. Among the different forms of cancer, research has reinforced a link between diabetes and the risk of breast cancer. Some studies have specifically linked diabetes to the highly aggressive, triple negative breast cancers (TNBCs) which do not respond to conventional hormonal/HER2 targeted interventions, have chances of early recurrence, metastasize, tend to be more invasive in nature and develop drug resistance. Commonly used anti-diabetic drugs, such as metformin, have recently gained importance in the treatment of breast cancer due to their proposed anti-cancer properties. Here we discuss the link between diabetes and breast cancer, the metabolic disturbances in diabetes that support the development of breast cancer, the challenges involved and future perspective and directions. We link the three main metabolic disturbances (dyslipidemia, hyperinsulinemia and hyperglycemia) that occur in diabetes to potential aberrant molecular pathways that may lead to the development of an oncogenic phenotype of the breast tissue, thereby leading to acceleration of cell growth, proliferation, migration, inflammation, angiogenesis, EMT and metastasis and inhibition of apoptosis in breast cancer cells. Furthermore, managing diabetes and treating cancer using a combination of anti-diabetic and classical anti-cancer drugs should prove to be more efficient in the treatment diabetes associated cancers.

Metformin: The Answer to Cancer in a Flower? Current Knowledge and Future Prospects of Metformin as an Anti-Cancer Agent in Breast Cancer

“…While it is well established that diabetes is linked to a higher risk of cardiovascular diseases, hepatic and renal complications, and nerve damage, much less appreciated is the fact that diabetes can be linked to a higher risk, incidence, progression, and post-treatment prognosis of different cancers [3][4][5][6][7]. More recently, owing to the many common risk factors attributable to both diabetes and cancer a convincing link was established, by several epidemiological studies, between the occurrence of diabetes and the higher risk and incidence of many different cancers, including the various types of breast cancer [5,[8][9][10][11][12]. In this regard, particularly in breast cancers, while insulin and insulin analogues used to treat diabetes propagated tumor growth through the induction of angiogenesis and activation of mitogenic signaling mechanisms and drugs such as thiazolidinediones do not appear to have a significant anti-cancer effect, metformin on the other hand exhibited significant anti-proliferative and anti-cancer effects [5].Metformin (1, 1-dimethylbiguanide) has its history traced back to the 18th century (year 1772), when Galega officinalis (commonly known as French Lilac/Goat's Rue/Spanish Safonin/False Indigo) was used to treat symptoms which was later attributed to diabetes [13,14].…”

“…More recently, owing to the many common risk factors attributable to both diabetes and cancer a convincing link was established, by several epidemiological studies, between the occurrence of diabetes and the higher risk and incidence of many different cancers, including the various types of breast cancer [5,[8][9][10][11][12]. In this regard, particularly in breast cancers, while insulin and insulin analogues used to treat diabetes propagated tumor growth through the induction of angiogenesis and activation of mitogenic signaling mechanisms and drugs such as thiazolidinediones do not appear to have a significant anti-cancer effect, metformin on the other hand exhibited significant anti-proliferative and anti-cancer effects [5].Metformin (1, 1-dimethylbiguanide) has its history traced back to the 18th century (year 1772), when Galega officinalis (commonly known as French Lilac/Goat's Rue/Spanish Safonin/False Indigo) was used to treat symptoms which was later attributed to diabetes [13,14]. While the hypoglycemic activity of Galega officinalis was attributed to the guanidine component by the 1800s, the apparent toxicity associated with the clinical use of guanidine led to synthesis, testing, and use of several biguanides, including dimethylbiguanide, for their glucose-lowering and anti-malarial effects and for the treatment of influenza in the late 1920s [13,14].…”

“…The confirmed anti-hyperglycemic effect (without causing hypoglycemia) and the favorable safety prolife when compared to phenformin and buformin helped metformin claim the title as the 'most widely prescribed and first-line oral anti-diabetic drug' and manages to keep that title 62 years after its first clinical use in the treatment and management of type 2 diabetes [13,14,19].Metformin decreases the levels of blood glucose by decreasing gluconeogenesis and glycogenolysis in the liver, decreasing the intestinal absorption of glucose, reducing the release of free fatty acids (FFA) from adipose tissue, and increasing glucose utilization by the muscle (Figure 1) [20]. Apart from its glucose-lowering effect, metformin was studied for its cardioprotective and vasculo-protective effects and more recently for its effects as a cancer preventive and anti-cancer/anti-tumor agent in different cancers (Figure 1) [5,20,21]. Depending on patient prolife and various disease conditions or stages, metformin treatment-associated beneficial effects in the treatment of hepatic diseases [22][23][24][25], renal damage and disorders [26], neurodegenerative diseases [27][28][29], and bone disorders [30] were reported.…”

“…In addition, metformin treatment-related antiaging effects, delay in the onset of age-related disorders, and improvement in longevity (lifespan) were reported in C. elegans, insects, and rodents [31][32][33][34].Interest has grown in studying the possible use of metformin as an anti-cancer/anti-tumor agent individually or in combination with frequently used chemotherapeutic agents and/or radiation. Epidemiological studies and meta-analysis data suggest that diabetic individuals on a metformin treatment regimen, to control their blood glucose levels, have a lower risk of developing cancers of all types and additionally individuals who are both diabetic and suffering from cancer and on metformin treatment have an improved response to chemotherapy and radiation therapy, better prognosis, and higher survival rates when compared to those who do not take metformin [5,[35][36][37][38][39][40][41][42]. In cancer cells, the ability of metformin to alter cancer metabolism and mitochondrial function and to modulate intracellular signaling activity related to key oncogenic pathways such as the Ras/Raf/MEK/ERK, PI3K/Akt, and mTOR pathways, retards cancer cell growth, proliferation, migration, increases cell death, and inhibits EMT, invasion, and metastasis [36,[43][44][45][46][47].…”

“…In cancer cells, the ability of metformin to alter cancer metabolism and mitochondrial function and to modulate intracellular signaling activity related to key oncogenic pathways such as the Ras/Raf/MEK/ERK, PI3K/Akt, and mTOR pathways, retards cancer cell growth, proliferation, migration, increases cell death, and inhibits EMT, invasion, and metastasis [36,[43][44][45][46][47]. While the activation of AMPK seems to Biomolecules 2019, 9, 846 3 of 33 be key to the many of the beneficial anti-cancer effects of metformin, AMPK independent effects have also been reported [5,36,[43][44][45]47]. However, most of the mechanistic data on the anti-cancer effects of metformin were derived from in vitro experiments using cancer cell lines and thus may not reflect the mode of action of metformin in an in vivo or clinical setting.Biomolecules 2019, 9, x FOR PEER REVIEW 3 of 40 Figure 1.…”