Doxorubicin-Resistant TNBC Cells Exhibit Rapid Growth with Cancer Stem Cell-like Properties and EMT Phenotype, Which Can Be Transferred to Parental Cells through Autocrine Signaling

Emerging evidence suggests that breast cancer stem cells (BCSCs), and epithelial–mesenchymal transition (EMT) may be involved in resistance to doxorubicin. However, it is unlear whether the doxorubicin-induced EMT and expansion of BCSCs is related to cancer dormancy, or outgrowing cancer cells with...

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Autores principales:	Anjugam Paramanantham, Eun-Joo Jung, Hye-Jung Kim, Bae-Kwon Jeong, Jin-Myung Jung, Gon-Sup Kim, Hong-Soon Chan, Won-Sup Lee
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	doxorubicin-resistant MDA-MB-231 breast cancer CSCs EGFR Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/ef69556288e244c5a4838ea8396ccaf5
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spelling	oai:doaj.org-article:ef69556288e244c5a4838ea8396ccaf52021-11-25T17:56:39ZDoxorubicin-Resistant TNBC Cells Exhibit Rapid Growth with Cancer Stem Cell-like Properties and EMT Phenotype, Which Can Be Transferred to Parental Cells through Autocrine Signaling10.3390/ijms2222124381422-00671661-6596https://doaj.org/article/ef69556288e244c5a4838ea8396ccaf52021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/22/12438https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Emerging evidence suggests that breast cancer stem cells (BCSCs), and epithelial–mesenchymal transition (EMT) may be involved in resistance to doxorubicin. However, it is unlear whether the doxorubicin-induced EMT and expansion of BCSCs is related to cancer dormancy, or outgrowing cancer cells with maintaining resistance to doxorubicin, or whether the phenotypes can be transferred to other doxorubicin-sensitive cells. Here, we characterized the phenotype of doxorubicin-resistant TNBC cells while monitoring the EMT process and expansion of CSCs during the establishment of doxorubicin-resistant MDA-MB-231 human breast cancer cells (DRM cells). In addition, we assessed the potential signaling associated with the EMT process and expansion of CSCs in doxorubicin-resistance of DRM cells. DRM cells exhibited morphological changes from spindle-shaped MDA-MB-231 cells into round-shaped giant cells. They exhibited highly proliferative, EMT, adhesive, and invasive phenotypes. Molecularly, they showed up-regulation of Cyclin D1, mesenchymal markers (β-catenin, and N-cadherin), MMP-2, MMP-9, ICAM-1 and down-regulation of E-cadherin. As the molecular mechanisms responsible for the resistance to doxorubicin, up-regulation of EGFR and its downstream signaling, were suggested. AKT and ERK1/2 expression were also increased in DRM cells with the advancement of resistance to doxorubicin. Furthermore, doxorubicin resistance of DRM cells can be transferred by autocrine signaling. In conclusion, DRM cells harbored EMT features with CSC properties possessing increased proliferation, invasion, migration, and adhesion ability. The doxorubicin resistance, and doxorubicin-induced EMT and CSC properties of DRM cells, can be transferred to parental cells through autocrine signaling. Lastly, this feature of DRM cells might be associated with the up-regulation of EGFR.Anjugam ParamananthamEun-Joo JungHye-Jung KimBae-Kwon JeongJin-Myung JungGon-Sup KimHong-Soon ChanWon-Sup LeeMDPI AGarticledoxorubicin-resistantMDA-MB-231breast cancerCSCsEGFRBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 12438, p 12438 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	doxorubicin-resistant MDA-MB-231 breast cancer CSCs EGFR Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	doxorubicin-resistant MDA-MB-231 breast cancer CSCs EGFR Biology (General) QH301-705.5 Chemistry QD1-999 Anjugam Paramanantham Eun-Joo Jung Hye-Jung Kim Bae-Kwon Jeong Jin-Myung Jung Gon-Sup Kim Hong-Soon Chan Won-Sup Lee Doxorubicin-Resistant TNBC Cells Exhibit Rapid Growth with Cancer Stem Cell-like Properties and EMT Phenotype, Which Can Be Transferred to Parental Cells through Autocrine Signaling
description	Emerging evidence suggests that breast cancer stem cells (BCSCs), and epithelial–mesenchymal transition (EMT) may be involved in resistance to doxorubicin. However, it is unlear whether the doxorubicin-induced EMT and expansion of BCSCs is related to cancer dormancy, or outgrowing cancer cells with maintaining resistance to doxorubicin, or whether the phenotypes can be transferred to other doxorubicin-sensitive cells. Here, we characterized the phenotype of doxorubicin-resistant TNBC cells while monitoring the EMT process and expansion of CSCs during the establishment of doxorubicin-resistant MDA-MB-231 human breast cancer cells (DRM cells). In addition, we assessed the potential signaling associated with the EMT process and expansion of CSCs in doxorubicin-resistance of DRM cells. DRM cells exhibited morphological changes from spindle-shaped MDA-MB-231 cells into round-shaped giant cells. They exhibited highly proliferative, EMT, adhesive, and invasive phenotypes. Molecularly, they showed up-regulation of Cyclin D1, mesenchymal markers (β-catenin, and N-cadherin), MMP-2, MMP-9, ICAM-1 and down-regulation of E-cadherin. As the molecular mechanisms responsible for the resistance to doxorubicin, up-regulation of EGFR and its downstream signaling, were suggested. AKT and ERK1/2 expression were also increased in DRM cells with the advancement of resistance to doxorubicin. Furthermore, doxorubicin resistance of DRM cells can be transferred by autocrine signaling. In conclusion, DRM cells harbored EMT features with CSC properties possessing increased proliferation, invasion, migration, and adhesion ability. The doxorubicin resistance, and doxorubicin-induced EMT and CSC properties of DRM cells, can be transferred to parental cells through autocrine signaling. Lastly, this feature of DRM cells might be associated with the up-regulation of EGFR.
format	article
author	Anjugam Paramanantham Eun-Joo Jung Hye-Jung Kim Bae-Kwon Jeong Jin-Myung Jung Gon-Sup Kim Hong-Soon Chan Won-Sup Lee
author_facet	Anjugam Paramanantham Eun-Joo Jung Hye-Jung Kim Bae-Kwon Jeong Jin-Myung Jung Gon-Sup Kim Hong-Soon Chan Won-Sup Lee
author_sort	Anjugam Paramanantham
title	Doxorubicin-Resistant TNBC Cells Exhibit Rapid Growth with Cancer Stem Cell-like Properties and EMT Phenotype, Which Can Be Transferred to Parental Cells through Autocrine Signaling
title_short	Doxorubicin-Resistant TNBC Cells Exhibit Rapid Growth with Cancer Stem Cell-like Properties and EMT Phenotype, Which Can Be Transferred to Parental Cells through Autocrine Signaling
title_full	Doxorubicin-Resistant TNBC Cells Exhibit Rapid Growth with Cancer Stem Cell-like Properties and EMT Phenotype, Which Can Be Transferred to Parental Cells through Autocrine Signaling
title_fullStr	Doxorubicin-Resistant TNBC Cells Exhibit Rapid Growth with Cancer Stem Cell-like Properties and EMT Phenotype, Which Can Be Transferred to Parental Cells through Autocrine Signaling
title_full_unstemmed	Doxorubicin-Resistant TNBC Cells Exhibit Rapid Growth with Cancer Stem Cell-like Properties and EMT Phenotype, Which Can Be Transferred to Parental Cells through Autocrine Signaling
title_sort	doxorubicin-resistant tnbc cells exhibit rapid growth with cancer stem cell-like properties and emt phenotype, which can be transferred to parental cells through autocrine signaling
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/ef69556288e244c5a4838ea8396ccaf5
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Doxorubicin-Resistant TNBC Cells Exhibit Rapid Growth with Cancer Stem Cell-like Properties and EMT Phenotype, Which Can Be Transferred to Parental Cells through Autocrine Signaling

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