RETRACTED: Metformin and Breast Cancer: Where Are We Now?

Abstract

Breast cancer is the most prevalent cancer and the leading cause of cancer-related death among women worldwide. Type 2 diabetes-associated metabolic traits such as hyperglycemia, hyperinsulinemia, inflammation, oxidative stress, and obesity are well-known risk factors for breast cancer. The insulin sensitizer metformin, one of the most prescribed oral antidiabetic drugs, has been suggested to function as an antitumoral agent, based on epidemiological and retrospective clinical data as well as preclinical studies showing an antiproliferative effect in cultured breast cancer cells and animal models. These benefits provided a strong rationale to study the effects of metformin in routine clinical care of breast cancer patients. However, the initial enthusiasm was tempered after disappointing results in randomized controlled trials, particularly in the metastatic setting. Here, we revisit the current state of the art of metformin mechanisms of action, critically review past and current metformin-based clinical trials, and briefly discuss future perspectives on how to incorporate metformin into the oncologist's armamentarium for the prevention and treatment of breast cancer.

Keywords: breast cancer; clinical trials; diabetes; insulin; metformin.

Figure 1

Antitumoral activity of the antidiabetic biguanide metformin. Metformin may affect tumorigenesis by acting on different hallmarks of cancer (angiogenesis, cell growth and proliferation, glucose metabolism, epithelial to mesenchymal transition, cell cycle progression, DNA damage or inflammation). These effects may be led by a direct (insulin-independent) effect mediated by the activation of AMPK. Metformin also has an indirect (insulin-dependent) effect, in which metformin reduces insulin levels. This leads to a decrease in blood glucose by limiting gluconeogenesis and increasing glycogenolysis in the liver, promoting growth hormone synthesis, reducing the release of free fatty acids from adipose tissue, and stimulating lipogenesis, as well as fostering glycogenesis, protein synthesis, and glucose utilization in the muscle.

Figure 2

Antiproliferative effects of metformin on breast cancer cells. The antiproliferative activity of metformin in breast cancer is partly attributed to its ability to reduce insulin/IGF1 levels, which inhibits the molecular pathways mediated by them that support tumor initiation and progression (indirect or insulin-dependent mechanism, represented via red lines ˗ ˗ ˗I). Metformin is transported into the cell via the organic cation transporters (OCTs), which support the intracellular accumulation of metformin. On the contrary, the transporters’ multidrug and toxin extrusion (MATE) expel metformin from the cell. Inside the cell, metformin directly activates AMPK and the ‘AMPK dependent’ effects (direct or insulin-independent effects, which are represented via black lines ˗ ˗ ˗I). This process includes the inhibition of IRS1 phosphorylation and blocking of MAPK and mTOR, among other pathways. Metformin is also known to inhibit mitochondrial Complex 1 of the electron transport chain, which reduces ATP levels and increases the AMP/ATP ratio, leading to further AMPK activation.