Muscarinic acetylcholine receptors as a double edged sword. Their role in tumorigenesis and in breast cancer treatment

ALEJANDRO ESPAÑOL; LOMBARDI G; MARTINEZ PULIDO, PAOLA; SALEM , AGUSTINA; MARÍA E. SALES

Simposio; 4th International Symposium on Non-neuronal Acetylcholine; 2014

It has been thoroughly documented that the non Neuronal Cholinergic System (nNCS) controls cancer progression. Particularly, we have demonstrated that muscarinic acetylcholine receptors (mAChR), as components of the nNCS are involved in breast cancer progression in different experimental models. In mice, we demonstrated that mAChR are expressed in three distinct spontaneous mammary adenocarcinomas, while they were absent in normal epithelial mammary cells. In humans, we detected the expression of mAChR in breast tumor homogenates as well as, in two different tumor cell lines MDA-MB-231 and in MCF-7. The latter exhibits a marked expression of 3 and 4 subtypes. To analyze the role of mAChR in human breast oncogenesis, we transfected  the non tumorigenic mammary cell line, MCF-10A, which does not express mAChR with these receptors and obtained three stable clones (MCF-10A-mAChR3, MCF-10A-mAChR4 and MCF-10A-mAChR3&4). These clones formed spheroid structures in vitro resembling MCF-7 cells and responded to the stimulation with carbachol. Similar results were observed when we analyze tumor growth in NUDE mice. Untransfected MCF-10A cells were unable to growth either in tridimensional culture or in NUDE mice. Taking into account these previous results, as well as the fact that the addition of a combination of paclitaxel plus carbachol at low concentrations to murine breast cancer cells promotes tumor cell lysis, mainly via apotosis, we analyzed the role of mAChR as therapeutic targets in human breast cancer treatment. We confirmed that this combination was equally useful to trigger cell death in MCF-7 and MDA-MB-231 human adenocarcinomas, while it was innocuous in MCF-10A cells. These results let us speculate, in the possibility of the use of this type of metronomic therapy in breast cancer.