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

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

Simposio; 4 th Internacional Symposium on non-neuronal acetylcholine; 2014

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