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Please use this identifier to cite or link to this item:
https://ir.csmu.edu.tw:8080/ir/handle/310902500/20267
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Title: | The expression and significance of insulin-like growth factor-1 receptor and its pathway on breast cancer stem/progenitors |
Authors: | Chang, Wen-Wei Lin, Ruey-Jen Yu, John Chang, Wen-Ying Fu, Chiung-Hui Lai, Alan Chuan-Ying Yu, Jyh-Cherng Yu, Alice L |
Keywords: | Breast Cancer;Rapamycin;Perifosine;ALDH Activity;BC0244 Cell |
Date: | 2013 |
Issue Date: | 2019-07-17T07:12:46Z (UTC)
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Publisher: | Breast Cancer Research |
ISSN: | 1465-542X |
Abstract: | Introduction
Dysregulation of the insulin-like growth factor-1 receptor (IGF-1R)/phosphatidylinositol-3-kinase (PI3K)/Akt pathway was shown to correlate with breast cancer disease progression. Cancer stem cells are a subpopulation within cancer cells that participate in tumor initiation, radio/chemoresistance and metastasis. In breast cancer, breast cancer stem cells (BCSCs) were identified as CD24-CD44+ cells or cells with high intracellular aldehyde dehydrogenase activity (ALDH+). Elucidation of the role of IGF-1R in BCSCs is crucial to the design of breast cancer therapies targeting BCSCs.
Methods
IGF-1R expression in BCSCs and noncancer stem cells sorted from xenografts of human primary breast cancers was examined by fluorescence-activated cell sorting (FACS), western blot analysis and immunoprecipitation. The role of IGF-1R in BCSCs was assessed by IGF-1R blockade with chemical inhibitor and gene silencing. Involvement of PI3K/Akt/mammalian target of rapamycin (mTOR) as the downstream pathway was studied by their phosphorylation status upon IGF-1R inhibition and the effects of chemical inhibitors of these signaling molecules on BCSCs. We also studied 16 clinical specimens of breast cancer for the expression of phosphor-Akt in the BCSCs by FACS.
Results
Expression of phosphorylated IGF-1R was greater in BCSCs than in non-BCSCs from xenografts of human breast cancer, which were supported by western blot and immunoprecipitation experiments. The sorted IGF-1R-expressing cells displayed features of cancer stem/progenitors such as mammosphere formation in vitro and tumorigenicity in vivo, both of which were suppressed by knockdown of IGF-1R. A specific inhibitor of the IGF-1R, picropodophyllin suppressed phospho-AktSer473 and preferentially decreased ALDH+ BCSC populations of human breast cancer cells. Furthermore, picropodophyllin inhibited the capacity of CD24-CD44+ BCSCs to undergo the epithelial-mesenchymal transition process with downregulation of mesenchymal markers. Inhibitors of signal molecules downstream of IGF-1R including PI3K/Akt/mTOR also reduced the ALDH+ population of breast cancer cells. Furthermore, the mTOR inhibitor, rapamycin, suppressed BCSCs in vitro and in vivo.
Conclusion
Our data support the notion that IGF-1R is a marker of stemness, and IGF-1R and its downstream PI3K/Akt/mTOR pathway are attractive targets for therapy directed against breast cancer stem/progenitors. |
URI: | https://ir.csmu.edu.tw:8080/ir/handle/310902500/20267 |
Relation: | Breast Cancer Research, 15, R39 |
Appears in Collections: | [生物醫學科學學系暨碩士班] 期刊論文
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