Markers of tumor-initiating cells predict chemoresistance in breast cancer.

<h4>Purpose</h4>Evidence is lacking whether the number of breast tumor-initiating cells (BT-ICs) directly correlates with the sensitivity of breast tumors to chemotherapy. Here, we evaluated the association between proportion of BT-ICs and chemoresistance of the tumors.<h4>Methods&...

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Autores principales:	Chang Gong, Herui Yao, Qiang Liu, Jingqi Chen, Junwei Shi, Fengxi Su, Erwei Song
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2010
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/17ee16d5b0d44ad0bb3a478aeac58cea
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spelling	oai:doaj.org-article:17ee16d5b0d44ad0bb3a478aeac58cea2021-11-18T07:01:29ZMarkers of tumor-initiating cells predict chemoresistance in breast cancer.1932-620310.1371/journal.pone.0015630https://doaj.org/article/17ee16d5b0d44ad0bb3a478aeac58cea2010-12-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21187973/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Purpose</h4>Evidence is lacking whether the number of breast tumor-initiating cells (BT-ICs) directly correlates with the sensitivity of breast tumors to chemotherapy. Here, we evaluated the association between proportion of BT-ICs and chemoresistance of the tumors.<h4>Methods</h4>Immunohistochemical staining(IHC) was used to examine the expression of aldehyde dehydrogenase 1 (ALDH1) and proliferating cell nuclear antigen, and TUNEL was used to detect the apoptosis index. The significance of various variables in patient survival was analyzed using a Cox proportional hazards model. The percentage of BT-ICs in breast cancer cell lines and primary breast tumors was determined by ALDH1 enzymatic assay, CD44(+)/CD24(-) phenotype and mammosphere formation assay.<h4>Results</h4>ALDH1 expression determined by IHC in primary breast cancers was associated with poor clinical response to neoadjuvant chemotherapy and reduced survival in breast cancer patients. Breast tumors that contained higher proportion of BT-ICs with CD44(+)/CD24(-) phenotype, ALDH1 enzymatic activity and sphere forming capacity were more resistant to neoadjuvant chemotherapy. Chemoresistant cell lines AdrR/MCF-7 and SK-3rd, had increased number of cells with sphere forming capacity, CD44(+)/CD24(-) phenotype and side-population. Regardless the proportion of T-ICs, FACS-sorted CD44(+)/CD24(-) cells that derived from primary tumors or breast cancer lines were about 10-60 fold more resistant to chemotherapy relative to the non- CD44(+)/CD24(-) cells and their parental cells. Furthermore, our data demonstrated that MDR1 (multidrug resistance 1) and ABCG2 (ATP-binding cassette sub-family G member 2) were upregulated in CD44(+)/CD24(-) cells. Treatment with lapatinib or salinomycin reduced the proportion of BT-ICs by nearly 50 fold, and thus enhanced the sensitivity of breast cancer cells to chemotherapy by around 30 fold.<h4>Conclusions</h4>These data suggest that the proportion of BT-ICs is associated with chemotherapeutic resistance of breast cancer. It highlights the importance of targeting T-ICs, rather than eliminating the bulk of rapidly dividing and terminally differentiated cells, in novel anti-cancer strategies.Chang GongHerui YaoQiang LiuJingqi ChenJunwei ShiFengxi SuErwei SongPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 5, Iss 12, p e15630 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Chang Gong Herui Yao Qiang Liu Jingqi Chen Junwei Shi Fengxi Su Erwei Song Markers of tumor-initiating cells predict chemoresistance in breast cancer.
description	<h4>Purpose</h4>Evidence is lacking whether the number of breast tumor-initiating cells (BT-ICs) directly correlates with the sensitivity of breast tumors to chemotherapy. Here, we evaluated the association between proportion of BT-ICs and chemoresistance of the tumors.<h4>Methods</h4>Immunohistochemical staining(IHC) was used to examine the expression of aldehyde dehydrogenase 1 (ALDH1) and proliferating cell nuclear antigen, and TUNEL was used to detect the apoptosis index. The significance of various variables in patient survival was analyzed using a Cox proportional hazards model. The percentage of BT-ICs in breast cancer cell lines and primary breast tumors was determined by ALDH1 enzymatic assay, CD44(+)/CD24(-) phenotype and mammosphere formation assay.<h4>Results</h4>ALDH1 expression determined by IHC in primary breast cancers was associated with poor clinical response to neoadjuvant chemotherapy and reduced survival in breast cancer patients. Breast tumors that contained higher proportion of BT-ICs with CD44(+)/CD24(-) phenotype, ALDH1 enzymatic activity and sphere forming capacity were more resistant to neoadjuvant chemotherapy. Chemoresistant cell lines AdrR/MCF-7 and SK-3rd, had increased number of cells with sphere forming capacity, CD44(+)/CD24(-) phenotype and side-population. Regardless the proportion of T-ICs, FACS-sorted CD44(+)/CD24(-) cells that derived from primary tumors or breast cancer lines were about 10-60 fold more resistant to chemotherapy relative to the non- CD44(+)/CD24(-) cells and their parental cells. Furthermore, our data demonstrated that MDR1 (multidrug resistance 1) and ABCG2 (ATP-binding cassette sub-family G member 2) were upregulated in CD44(+)/CD24(-) cells. Treatment with lapatinib or salinomycin reduced the proportion of BT-ICs by nearly 50 fold, and thus enhanced the sensitivity of breast cancer cells to chemotherapy by around 30 fold.<h4>Conclusions</h4>These data suggest that the proportion of BT-ICs is associated with chemotherapeutic resistance of breast cancer. It highlights the importance of targeting T-ICs, rather than eliminating the bulk of rapidly dividing and terminally differentiated cells, in novel anti-cancer strategies.
format	article
author	Chang Gong Herui Yao Qiang Liu Jingqi Chen Junwei Shi Fengxi Su Erwei Song
author_facet	Chang Gong Herui Yao Qiang Liu Jingqi Chen Junwei Shi Fengxi Su Erwei Song
author_sort	Chang Gong
title	Markers of tumor-initiating cells predict chemoresistance in breast cancer.
title_short	Markers of tumor-initiating cells predict chemoresistance in breast cancer.
title_full	Markers of tumor-initiating cells predict chemoresistance in breast cancer.
title_fullStr	Markers of tumor-initiating cells predict chemoresistance in breast cancer.
title_full_unstemmed	Markers of tumor-initiating cells predict chemoresistance in breast cancer.
title_sort	markers of tumor-initiating cells predict chemoresistance in breast cancer.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/17ee16d5b0d44ad0bb3a478aeac58cea
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Markers of tumor-initiating cells predict chemoresistance in breast cancer.

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