Bridging the Gap: the role of MDM2 inhibition in overcoming treatment resistance in breast cancer.

Murine double minute 2 (MDM2) is a protein that plays a crucial role in the regulation of the tumor suppressor p53. It is involved in several biological processes and in cancer development, both in a p53-dependent and independent manner. Discordant evidence exists on MDM2 genetic polymorphisms and a possible susceptibility to breast cancer, but more studies are needed to fully understand this relationship. Elevated MDM2 levels, due to gene amplification or overexpression, can be found in up to 40% of estrogen receptor positive breast cancers. These alterations exert antiapoptotic activity, promoting cell survival and resistance to treatment, through the degradation of p53. For this reason, evidence about MDM2 activity as an oncogene led to various approaches to counter its action in cancer. Several MDM2 inhibitors have been evaluated in in-vitro and in-vivo preclinical models, showing preliminary anticancer activity in various neoplasms, including breast cancer. Few of these agents have been tested in early phase clinical trials, alone or in combination, with some promising results, however showing significant drug toxicity. Wild type p53 may represent a potential biomarker of response. However, other biomarkers must be discovered to clearly select patients who can benefit from these therapies and new strategies are needed to manage their toxicity. In conclusion, further research is needed to fully understand the role of MDM2 in breast cancer and to develop targeted therapies that can effectively inhibit its function and at the same time limit the toxicity of so far experimented compounds.