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Estrogen Receptor α Mediates Doxorubicin Sensitivity in Breast Cancer Cells by Regulating E-Cadherin

Anthracyclines resistance is commonly seen in patients with estrogen receptor α (ERα) positive breast cancer. Epithelial-mesenchymal transition (EMT), which is characterized with the loss of epithelial cell polarity, cell adhesion and acquisition of new invasive property, is considered as one of the...

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Autores principales: Wan, Xiaoqing, Hou, Jiaxin, Liu, Shurong, Zhang, Yanli, Li, Wenqing, Zhang, Yanru, Ding, Yi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889969/
https://www.ncbi.nlm.nih.gov/pubmed/33614637
http://dx.doi.org/10.3389/fcell.2021.583572
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author Wan, Xiaoqing
Hou, Jiaxin
Liu, Shurong
Zhang, Yanli
Li, Wenqing
Zhang, Yanru
Ding, Yi
author_facet Wan, Xiaoqing
Hou, Jiaxin
Liu, Shurong
Zhang, Yanli
Li, Wenqing
Zhang, Yanru
Ding, Yi
author_sort Wan, Xiaoqing
collection PubMed
description Anthracyclines resistance is commonly seen in patients with estrogen receptor α (ERα) positive breast cancer. Epithelial-mesenchymal transition (EMT), which is characterized with the loss of epithelial cell polarity, cell adhesion and acquisition of new invasive property, is considered as one of the mechanisms of chemotherapy-induced drug resistance. In order to identify factors that associated with doxorubicin resistance, we performed in vitro and in vivo experiments using human and mouse breast cancer cell lines with different ERα status. Cell survival experiments revealed that ERα-positive cells (MCF-7 and MCF-7/ADR cell lines), were less sensitive to doxorubicin than ERα-negative (MDA-MB-231, MDA-MB-468) cells, and mouse mammary carcinoma cells (4T-1). The expression of E-cadherin reduced in low-invasive ERα-positive MCF-7 cells after treatment with doxorubicin, indicating epithelial mesenchymal transition. In contrast, the expression of E-cadherin was upregulated in high-invasive ERα-negative cells, showing mesenchymal-epithelial transition (MET). Moreover, it was found that the growth inhibition of 4T-1 cells by doxorubicin was positively correlated with the expression of E-cadherin. In a mouse breast cancer xenograft model, E-cadherin was overexpressed in the primary tumor tissues of the doxorubicin-treated mice. In ERα-positive MCF-7 cells, doxorubicin treatment upregulated the expression of EMT-related transcription factors Snail and Twist, that regulate the expression of E-cadherin. Following overexpression of ERα in ERα-negative cells (MDA-MB-231 and MDA-MB-468), doxorubicin enhanced the upregulation of Snail and Twist, decreased expression of E-cadherin, and decreased the sensitivity of cells to doxorubicin. In contrast, inhibition of ERα activity increased the sensitivity to doxorubicin in ERα-positive MCF-7 cells. These data suggest that the regulation of Snail and/or Twist varies depends on different ERα status. Therefore, doxorubicin combined with anti-estrogen receptor α therapy could improve the treatment efficacy of doxorubicin in ERα-positive breast cancer.
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spelling pubmed-78899692021-02-19 Estrogen Receptor α Mediates Doxorubicin Sensitivity in Breast Cancer Cells by Regulating E-Cadherin Wan, Xiaoqing Hou, Jiaxin Liu, Shurong Zhang, Yanli Li, Wenqing Zhang, Yanru Ding, Yi Front Cell Dev Biol Cell and Developmental Biology Anthracyclines resistance is commonly seen in patients with estrogen receptor α (ERα) positive breast cancer. Epithelial-mesenchymal transition (EMT), which is characterized with the loss of epithelial cell polarity, cell adhesion and acquisition of new invasive property, is considered as one of the mechanisms of chemotherapy-induced drug resistance. In order to identify factors that associated with doxorubicin resistance, we performed in vitro and in vivo experiments using human and mouse breast cancer cell lines with different ERα status. Cell survival experiments revealed that ERα-positive cells (MCF-7 and MCF-7/ADR cell lines), were less sensitive to doxorubicin than ERα-negative (MDA-MB-231, MDA-MB-468) cells, and mouse mammary carcinoma cells (4T-1). The expression of E-cadherin reduced in low-invasive ERα-positive MCF-7 cells after treatment with doxorubicin, indicating epithelial mesenchymal transition. In contrast, the expression of E-cadherin was upregulated in high-invasive ERα-negative cells, showing mesenchymal-epithelial transition (MET). Moreover, it was found that the growth inhibition of 4T-1 cells by doxorubicin was positively correlated with the expression of E-cadherin. In a mouse breast cancer xenograft model, E-cadherin was overexpressed in the primary tumor tissues of the doxorubicin-treated mice. In ERα-positive MCF-7 cells, doxorubicin treatment upregulated the expression of EMT-related transcription factors Snail and Twist, that regulate the expression of E-cadherin. Following overexpression of ERα in ERα-negative cells (MDA-MB-231 and MDA-MB-468), doxorubicin enhanced the upregulation of Snail and Twist, decreased expression of E-cadherin, and decreased the sensitivity of cells to doxorubicin. In contrast, inhibition of ERα activity increased the sensitivity to doxorubicin in ERα-positive MCF-7 cells. These data suggest that the regulation of Snail and/or Twist varies depends on different ERα status. Therefore, doxorubicin combined with anti-estrogen receptor α therapy could improve the treatment efficacy of doxorubicin in ERα-positive breast cancer. Frontiers Media S.A. 2021-02-04 /pmc/articles/PMC7889969/ /pubmed/33614637 http://dx.doi.org/10.3389/fcell.2021.583572 Text en Copyright © 2021 Wan, Hou, Liu, Zhang, Li, Zhang and Ding. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Wan, Xiaoqing
Hou, Jiaxin
Liu, Shurong
Zhang, Yanli
Li, Wenqing
Zhang, Yanru
Ding, Yi
Estrogen Receptor α Mediates Doxorubicin Sensitivity in Breast Cancer Cells by Regulating E-Cadherin
title Estrogen Receptor α Mediates Doxorubicin Sensitivity in Breast Cancer Cells by Regulating E-Cadherin
title_full Estrogen Receptor α Mediates Doxorubicin Sensitivity in Breast Cancer Cells by Regulating E-Cadherin
title_fullStr Estrogen Receptor α Mediates Doxorubicin Sensitivity in Breast Cancer Cells by Regulating E-Cadherin
title_full_unstemmed Estrogen Receptor α Mediates Doxorubicin Sensitivity in Breast Cancer Cells by Regulating E-Cadherin
title_short Estrogen Receptor α Mediates Doxorubicin Sensitivity in Breast Cancer Cells by Regulating E-Cadherin
title_sort estrogen receptor α mediates doxorubicin sensitivity in breast cancer cells by regulating e-cadherin
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889969/
https://www.ncbi.nlm.nih.gov/pubmed/33614637
http://dx.doi.org/10.3389/fcell.2021.583572
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