Acetylcholine, Another Factor in Breast Cancer
1
Laboratorio de Bioquímica, Departamento de Química, Facultad de Ciencias, Universidad de Tarapacá, Arica 1000007, Chile
2
Instituto de Alta Investigación, Universidad de Tarapacá, Arica 1000000, Chile
*
Author to whom correspondence should be addressed.
Biology 2023, 12(11), 1418; https://doi.org/10.3390/biology12111418
Submission received: 3 October 2023
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Revised: 8 November 2023
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Accepted: 9 November 2023
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Published: 11 November 2023
Simple Summary
Our previous work established that organophosphorus pesticides increased acetylcholine (ACh) levels and promoted mammary gland tumor development in rats. This suggests that ACh could modulate ERα activity. In this study, we demonstrated that ACh has functional effects in breast cancer cell lines—specifically, activating the MAPK/ERK and PI3K/Akt pathways, inducing p-ERα, and eliciting its nuclear translocation. However, ACh did not induce the upregulation of estrogen-responsive genes, suggesting a mechanistic distinction from the effects of 17β-estradiol. Furthermore, ACh enhanced cell viability and induced the overexpression of specific EMT markers. These findings suggest that ACh and muscarinic receptors could be emerging regulators of breast cancer.
Abstract
Acetylcholine (ACh) is a neurotransmitter that regulates multiple functions in the nervous system, and emerging evidence indicates that it could play a role in cancer progression. However, this function is controversial. Previously, we showed that organophosphorus pesticides decreased the levels of the enzyme acetylcholinesterase in vivo, increasing ACh serum levels and the formation of tumors in the mammary glands of rats. Furthermore, we showed that ACh exposure in breast cancer cell lines induced overexpression of estrogen receptor alpha (ERα), a key protein described as the master regulator in breast cancer. Therefore, here, we hypothesize that ACh alters the ERα activity through a ligand-independent mechanism. The results here reveal that the physiological concentration of ACh leads to the release of Ca+2 and the activity of MAPK/ERK and PI3K/Akt pathways. These changes are associated with an induction of p-ERα and its recruitment to the nucleus. However, ACh fails to induce overexpression of estrogen-responsive genes, suggesting a different activation mechanism than that of 17ß-estradiol. Finally, ACh promotes the viability of breast cancer cell lines in an ERα-dependent manner and induces the overexpression of some EMT markers. In summary, our results show that ACh promotes breast cancer cell proliferation and ERα activity, possibly in a ligand-independent manner, suggesting its putative role in breast cancer progression.
