An old but effective drug against diabetes can also help in the fight against breast cancer. Probably, if administered to healthy women it can prevent its insurgence. These are the important results of a study on metformin just published on Nature Communication, and conducted by the team of Giovanni Blandino of the National Cancer Institute Regina Elena (IRCCS). In this work metformin exerts some of its antitumor activities by reprogramming the metabolism of a tumor cell.

Metformin is a drug widely used in patients with type II diabetes mellitus; it sensitizes the tissue to insulin and reduces blood glucose levels by inhibiting hepatic glucose production. It works by activating the AMPK enzyme, which induces the muscles to use glucose in the blood. There are many studies showing that diabetic patients treated with metformin are less likely to develop breast cancer. An important aspect lies in the fact that among the many drugs used for treating diabetes only metformin has this type of effect. "To understand the molecular basis of this protective activity we studied the metabolism of tumor cells after treatment with metformin, and then tried to understand which molecular mediators are activated". By treating mice which had been implanted SUM159PT tumor cells, with metformin the tumor proliferation index appears to be much less than in control mice; it is also interesting to note that no toxic effects were found in mice treated with the drug.

Here is how it works

In order to understand which molecular mediators are at the basis of of the metformin action, cutting edge technology of molecular biology was used. This was possible thanks to collaborations with other research groups, including the team headed by Paola Muti of Harvard University. According to the study, metformin performs its function by acting on microRNAs. MicroRNAs are short, stable non-coding RNAs that target the mRNA of coding genes in order to degrade it, thus reducing the levels of gene products. MicroRNAs modulation represents an effective strategy to quickly reduce the levels of gene products. Metformin action needs the DICER enzyme. In mice deprived of this enzyme, involved in the system of RNA molecule degradation, the drug does not exert its anticancer function. This suggests that metformin's action promotes DICER.

Metformin inhibits c-myc messenger RNA, which is the primary metabolism regulator of tumor cells due to its effect on anabolic pathways. Tumor cells produce energy in a different way compared to normal adult cells, a process that converts glucose to lactate. This allows tumor cells to proliferate rapidly even when oxygen levels are not optimal. Metformin can reprogram the anabolic metabolism of tumor cells into the physiological catabolic metabolism. "Understanding that metformin plays a key role in restoring metabolism may be a decisive step for the treatment of many tumors.The first trials concerned breast cancer but, Blandino explains "studies on cell cultures, which have not yet been published, show that metformin can be used for the treatment of other tumors such as sarcomas".

Tumor cells treated with this drug become normal cells again. Treating tumors with regulators of metabolism may be a very important step forward, considering that many people who suffer from metabolic disorders such as obesity, develop tumors easily. The molecular data produced in this work will be relevant to understand what dose of metformin will be most suitable for administration to humans in the treatment of some neoplasms, but also to try developing drugs that can prevent its occurrence.

A drug for prevention: the Tevere project

This research is part of the Tevere project - which was launched precisely with the aim to test metformin in the prevention of breast cancer and cardiovascular diseases in postmenopausal women.

Launched about two years ago, with funding from the Ministry of Health, and the participation of the National Cancer Institute of Milan and the European Institute of Oncology in Catania, the objective of the project is to determine whether metformin can be used as a chemopreventive drug. Also a special diet aimed at reducing the levels of insulin and sexual hormones may improve metabolic conditions that predispose to breast cancer (a direction followed in particular by Franco Berrino of the National Cancer Institute of Milan).

The chemoprevention trials provided by the project consist in administering metformin twice daily for 5 years to healthy women. "Organizing the trial," explains Blandino, "was not easy given the innovative nature of the project. Indeed, we are not testing the effect of a drug on sick patients but on healthy people. Unlike other clinical trials that are being developed in U.S. and UK centres, the Tevere Project is the only one in the world to use metformin as a primary prevention".

Recruitment was meticulous, the selection of volunteers implied precise requirements: they had to have entered menopause and be healthy. Currently trials are carried out on 200 women in two centers in Sicily and one in Milan; the future goal will be to increase the number of recruited women up to more than 16,000 women. Over the next months a center will be opened also in Canada.

The article on Nature Communication (read the abstract).