Basic Study
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Oncol. Jun 24, 2022; 13(6): 505-519
Published online Jun 24, 2022. doi: 10.5306/wjco.v13.i6.505
Nicotinic receptors modulate antitumor therapy response in triple negative breast cancer cells
Alejandro Español, Yamila Sanchez, Agustina Salem, Jaqueline Obregon, Maria Elena Sales
Alejandro Español, Yamila Sanchez, Agustina Salem, Jaqueline Obregon, Maria Elena Sales, Laboratory of Immunopharmacology and Tumor Biology, CEFYBO CONICET University of Buenos Aires, Buenos Aires C1121ABG, Argentina
Author contributions: Español A performed cell assays, supervised the work, analyzed and interpreted the data, and wrote the manuscript; Sanchez Y and Salem A performed cell assays and contributed to the writing of the manuscript; Obregon J carried out lab work as part of her grade thesis, and helped to analyze and interpret the data; Sales ME supervised the work and edited the manuscript draft; all authors read and approved the final manuscript.
Supported by University of Buenos Aires (UBA) UBACYT 2018-2022, No. 20020170100227; National Research Council (CONICET) PIP 2015-2017, No. 2015-0239; and National Agency for Scientific and Technological Promotion (ANPCyT) PICT 2015-2017, No. 2015-2396.
Institutional review board statement: In the realization of the manuscript, no human samples or patients were used, so the authorization of the Institutional Review Board was not required.
Institutional animal care and use committee statement: In the realization of the manuscript, no animals were used, so the authorization of the Institutional Animal Care and Use Committee was not required.
Conflict-of-interest statement: The authors certify that they have no conflicts of interest (including but not limited to commercial, personal, political, intellectual or religious interests) for this article.
Data sharing statement: The technical appendix, statistical code, and dataset are available from the corresponding author at Participants gave informed consent for data sharing.
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 16th Floor, Buenos Aires C1121ABG, Argentina.
Received: December 27, 2021
Peer-review started: December 27, 2021
First decision: February 15, 2022
Revised: February 24, 2022
Accepted: April 26, 2022
Article in press: April 26, 2022
Published online: June 24, 2022

Triple negative breast cancer is more aggressive than other breast cancer subtypes and constitutes a public health problem worldwide since it has high morbidity and mortality due to the lack of defined therapeutic targets. Resistance to chemotherapy complicates the course of patients’ treatment. Several authors have highlighted the participation of nicotinic acetylcholine receptors (nAChR) in the modulation of conventional chemotherapy treatment in cancers of the airways. However, in breast cancer, less is known about the effect of nAChR activation by nicotine on chemotherapy treatment in smoking patients.


To investigate the effect of nicotine on paclitaxel treatment and the signaling pathways involved in human breast MDA-MB-231 tumor cells.


Cells were treated with paclitaxel alone or in combination with nicotine, administered for one or three 48-h cycles. The effect of the addition of nicotine (at a concentration similar to that found in passive smokers’ blood) on the treatment with paclitaxel (at a therapeutic concentration) was determined using the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The signaling mediators involved in this effect were determined using selective inhibitors. We also investigated nAChR expression, and ATP “binding cassette” G2 drug transporter (ABCG2) expression and its modulation by the different treatments with Western blot. The effect of the treatments on apoptosis induction was determined by flow cytometry using annexin-V and 7AAD markers.


Our results confirmed that treatment with paclitaxel reduced MDA-MB-231 cell viability in a concentration-dependent manner and that the presence of nicotine reversed the cytotoxic effect induced by paclitaxel by involving the expression of functional α7 and α9 nAChRs in these cells. The action of nicotine on paclitaxel treatment was linked to modulation of the protein kinase C, mitogen-activated protein kinase, extracellular signal-regulated kinase, and NF-κB signaling pathways, and to an up-regulation of ABCG2 protein expression. We also detected that nicotine significantly reduced the increase in cell apoptosis induced by paclitaxel treatment. Moreover, the presence of nicotine reduced the efficacy of paclitaxel treatment administered in three cycles to MDA-MB-231 tumor cells.


Our findings point to nAChRs as responsible for the decrease in the chemotherapeutic effect of paclitaxel in triple negative tumors. Thus, nAChRs should be considered as targets in smoking patients.

Keywords: Breast cancer, Paclitaxel, Nicotinic acetylcholine receptors, Drug therapy, Signal transduction, Drug transporter

Core Tip: Smokers with lung tumors are more likely to generate resistance to chemotherapy than non-smokers. However, little is known about the effect of nicotinic activation during the treatment of breast cancer, a cancer which arises close to the lung. In triple negative human breast cells, nicotine reduces the chemotherapeutic effect of paclitaxel through the participation of several kinases, as well as by modulating ATP “binding cassette” G2 drug transporter expression and inducing resistance to treatment. These results indicate that nicotinic acetylcholine receptors are a new possible target in antitumor therapy for this subtype of breast cancer.