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
Research background

Triple negative is the subtype of breast cancer with the worst prognosis, showing an increase in resistance to chemotherapy in smoking patients, who have high levels of nicotine in their blood. In lung cancer, it has been proposed that the activation of nicotinic acetylcholine receptors could be responsible for the modulation of several parameters of tumor biology and the loss of effectiveness of chemotherapeutic treatment, but it is not known what occurs in a nearby organ such as the breast.

Research motivation

Given that breast tumor-bearing patients have a low efficiency to antitumor therapy, knowledge of the signaling pathways involved in this phenomenon is important to generate new therapeutic targets that improve sensitivity to treatment.

Research objectives

This research aimed to determine the signaling pathways involved in the nicotinic modulation of the cytostatic effect of paclitaxel in human triple negative breast cancer cells.

Research methods

The modulatory effect of nicotine on paclitaxel treatment was assessed by the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The trypan blue exclusion assay was used to evaluate viable cells in response to different treatments. Protein expression levels were evaluated by Western blot assays and apoptosis was determined using immunofluorescence assays with annexin V and 7AAD.

Research results

Nicotine decreased paclitaxel’s inhibition of viability and apoptosis in MDA-MB-231 breast cancer cells. This modulation of viability is mediated by the activation of α7 and α9 nicotinic acetylcholine receptors and protein kinases PKC, Ras, MEK, ERK, p38MAPK and the NF-κB pathway. Cells surviving paclitaxel treatment in the presence of nicotine are less sensitive to another cycle with the chemotherapeutic agent probably due an increase in the protein expression of ATP binding cassette transporter G2.

Research conclusions

Nicotine modulates the cytotoxic/apoptotic effects of paclitaxel and knowledge of its signaling pathway mediators could allow the development of better strategies to improve triple negative breast cancer therapy, such as nicotinic acetylcholine receptors blockage together with paclitaxel during chemotherapy administration to smoking patients.

Research perspectives

Knowledge of the mediators that participate in the nicotinic modulation of paclitaxel’s effect will allow the development of new antitumor strategies that could be applied not only to other subtypes of mammary tumors, but also to tumors in other organs of smoking patients.