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.

Metformin counteracts stimulatory effects induced by insulin in primary breast cancer cells

“…Moreover, metformin may modify the expression of main pro-tumorigenic genes and exert a synergic action with chemotherapeutics in BC cells [ 83 – 87 ]. Therefore, metformin has been suggested as a potential antitumoral agent in BC also considering the results of epidemiological studies in both diabetic and non-diabetic women [ 20 , 26 , 88 – 90 ]. Cumulatively, these data recently paved the way for numerous trials aimed at investigating whether patients with diverse BC subtypes may take advantage from the use of metformin either alone or in combination with chemotherapeutics.…”

“…Epidemiological and retrospective clinical data have demonstrated that a first-line drug for T2D, namely metformin, is associated with a low risk of BC and reduced cancer-related mortality rate in T2D patients [ 19 – 23 ]. Accordingly, extensive preclinical studies have indicated that metformin may exert antitumor effects in BC cells through both direct (insulin-independent) and indirect (insulin-dependent) mechanisms [ 24 – 26 ]. One of the well-accepted insulin-independent effects of metformin involves the activation of adenosine monophosphate activated protein kinase (AMPK), which in turn downregulates main insulin-stimulated transduction pathways, such as IRS1 and PI3K/AKT/mTOR transduction signaling [ 25 ].…”

“…One of the well-accepted insulin-independent effects of metformin involves the activation of adenosine monophosphate activated protein kinase (AMPK), which in turn downregulates main insulin-stimulated transduction pathways, such as IRS1 and PI3K/AKT/mTOR transduction signaling [ 25 ]. Furthermore, it has been reported that IR expression status, which is frequently related to insulin levels, may represent a predictive factor of the antitumoral activity of metformin [ 23 , 26 ].…”

Metformin and long non-coding RNAs in breast cancer

“…Metformin leads to reprograming of lipid metabolism, as a hallmark of cancer, by increase in acetyl-CoA carboxylase (ACC) and fatty acid synthase (FASN), and miRNA regulation [ 58 ]. It also inhibits Complex I of the mitochondria and increases the AMP/ATP ratio which leads to further AMPK activation [ 59 ]. The anti-BC effects of metformin have been illustrated in Fig.…”

Inflammatory Breast Cancer: The Cytokinome of Post-Mastectomy Wound Fluid Augments Proliferation, Invasion, and Stem Cell Markers

“…Breast cancer is associated with a high mortality in women worldwide [ 1 ]. Breast cancer treatment is based on several factors, including cancer stage, size, and metastasis [ 2 ].…”