Metformin: a therapeutic opportunity in breast cancer

Abstract

Two important, related pathways are involved in cancer growth: the insulin/insulin-like growth factor-1 (IGF1) signaling pathway, which is activated when nutrients are available, and the adenosine mono-phosphate-activated protein kinase (AMPK) pathway, activated when cells are starved for carbohydrates. Metformin inhibits transcription of key gluconeogenesis genes in the liver, increases glucose uptake in skeletal muscle, and decreases circulating insulin levels. Metformin reduces levels of circulating glucose, increases insulin sensitivity, and reduces insulin resistance-associated hyperinsulinemia. At the level of cell signaling, metformin activates AMPK. There are extensive preclinical data showing the anticancer effects of metformin in all breast cancer subtypes as well as in cytotoxic therapy-resistant models. These data, and the epidemiological and retrospective data supporting the antineoplastic effects of metformin, provide the rationale to study the role of metformin for breast cancer therapy in a variety of clinical settings.

Figure 1

Mechanisms of action of metformin. Metformin appears to exert its cell growth-inhibitory effects through two distinct mechanisms. A direct mechanism that inhibits the mTOR pathway and an indirect mechanism depending on insulin levels. Metformin activates adenosine monophosphate activated protein kinase (AMPK), the cellular energy sensor. Activation of AMPK leads to suppression of many of the processes highly dependent on ATP, such as gluconeogenesis, protein, fatty acid, and cholesterol biosynthesis. It inhibits transcription of gluconeogenesis genes in the liver and increases glucose uptake in skeletal muscle. This appears to reduce the levels of circulating glucose, increase insulin sensitivity, and reduce the hyperinsulinemia associated with insulin resistance. In the cancer cell, the mammalian target of rapamycin (mTOR) signaling pathway promotes cell growth and proliferation by interplay of two opposing upstream pathways involving the Akt pathway, which signals availability of nutrients, and the AMPK pathway, which signals lack of energy. TOR complex 1 (TORC1), directly regulates cell growth and contains raptor (regulatory associated protein of mTOR) and PRAS40 (proline-rich Akt substrate of 40 kDa), which represses mTOR activity. There are two types of input that activateTORC1: increased availability of amino acids at the cellular level, and activated insulin or the related growth factor IGF1 signaling. They activate phosphatidylinositol-3-kinase (PI3K) which switches on Akt. TORC1 is stimulated by the active, GTP-bound form of the Rheb, and immediately upstream of Rheb is the TSC1:TSC2 heterodimer. TSC2 converts Rheb to its inactive Rheb:GDP form. Activation of Akt causes phosphorylation of TSC2, which is thought to inhibit its GAP activity and stimulates TORC1. On the other hand, Akt also phosphorylates PRAS40 and appears to relieve its inhibitory effect. AMPK is activated when ATP levels lower switching off the mTOR pathway over the positive effects of amino acids or growth factors via phosphorylation of TSC2 by AMPK which stimulatesits Rheb-GAP activity. Metformin and its analogs also activate AMPK in the absence of TSC2 thought Raptor phosphorylation. This effect appears to be a direct effect on mTOR kinase activity, possibly involving increased binding of 14-3-3 proteins and/or partial dissociation of PRAS40. So, the AMPK pathway exerts two inhibitory effects on mTOR via phosphorylation of TSC2 and Raptor similary to the Akt pathway, which exerts two stimulatory effects via phosphorylation of TSC2 and PRAS40.