Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Oncol. Jun 24, 2021; 12(6): 404-428
Published online Jun 24, 2021. doi: 10.5306/wjco.v12.i6.404
Breast cancer: Muscarinic receptors as new targets for tumor therapy
Alejandro Español, Agustina Salem, Yamila Sanchez, María Elena Sales
Alejandro Español, Agustina Salem, Yamila Sanchez, María Elena Sales, Laboratory of Immunopharmacology and Tumor Biology, CEFYBO CONICET University of Buenos Aires, Buenos Aires C1121ABG, Argentina
Author contributions: Español A contributed to the writing of the manuscript and collected the data; Salem A contributed to the writing of the manuscript; Sanchez Y contributed to the writing of the manuscript; Sales ME contributed to the writing of the manuscript and collected the data.
Supported by National Agency for Scientific and Technological Promotion (ANPCyT), No. 2015-2396.
Conflict-of-interest statement: Authors declare no conflict of interests for this article.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Alejandro Español, PhD, Research Scientist, Laboratory of Immunopharmacology and Tumor Biology, CEFYBO CONICET University of Buenos Aires, Paraguay 2155 piso 16 Sector izq, Buenos Aires C1121ABG, Argentina.
Received: February 17, 2021
Peer-review started: February 17, 2021
First decision: March 17, 2021
Revised: March 26, 2021
Accepted: June 2, 2021
Article in press: June 2, 2021
Published online: June 24, 2021

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.