Breast cancer: Muscarinic receptors as new targets for tumor therapy

Abstract

The development of breast cancer is a complex process that involves the participation of different factors. Several authors have demonstrated the overexpression of muscarinic acetylcholine receptors (mAChRs) in different tumor tissues and their role in the modulation of tumor biology, positioning them as therapeutic targets in cancer. The conventional treatment for breast cancer involves surgery, radiotherapy, and/or chemotherapy. The latter presents disadvantages such as limited specificity, the appearance of resistance to treatment and other side effects. To prevent these side effects, several schedules of drug administration, like metronomic therapy, have been developed. Metronomic therapy is a type of chemotherapy in which one or more drugs are administered at low concentrations repetitively. Recently, two chemotherapeutic agents usually used to treat breast cancer have been considered able to activate mAChRs. The combination of low concentrations of these chemotherapeutic agents with muscarinic agonists could be a useful option to be applied in breast cancer treatment, since this combination not only reduces tumor cell survival without affecting normal cells, but also decreases pathological neo-angiogenesis, the expression of drug extrusion proteins and the cancer stem cell fraction. In this review, we focus on the previous evidences that have positioned mAChRs as relevant therapeutic targets in breast cancer and analyze the effects of administering muscarinic agonists in combination with conventional chemotherapeutic agents in a metronomic schedule.

Keywords: Muscarinic receptors; Drug therapy; Breast cancer; Drug combination; Metronomic therapy; Drug resistance

Core Tip: Muscarinic acetylcholine receptors should be considered as new targets in breast cancer therapy since they are expressed in breast tumor tissue but not in normal tissue. The addition of muscarinic agonists at low concentrations combined with traditional chemotherapeutic drugs presents promising results. The administration of these combinations in a metronomic schedule is effective to kill tumor cells, reduce tumor invasion and neoangiogenesis. Promising results have also been reported regarding the expression of drug extrusion pumps and the decrease of the cancer stem cell fraction, which would be useful to reduce resistance to traditional chemotherapy and the relapse of breast cancer.