The expression and significance of insulin-like growth factor-1 receptor and its pathway on breast cancer stem/progenitors.

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.

• Authors: Wen-Wei Chang, Ruey-Jen Lin, John Yu, Wen-Ying Chang, Chiung-Hui Fu, Alan Lai, Jyh-Cherng Yu, Alice L Yu
• Journal: Breast cancer research : BCR (Breast Cancer Res) Vol. 15 Issue 3 Pg. R39 (May 12 2013) ISSN: 1465-542X [Electronic] England
• PMID: 23663564 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• picropodophyllin
• Insulin-Like Growth Factor I
• Phosphatidylinositol 3-Kinases
• Receptor, IGF Type 1
• Proto-Oncogene Proteins c-akt
• Podophyllotoxin

Topics

• Animals
• Breast Neoplasms (drug therapy, genetics, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Insulin-Like Growth Factor I (genetics, metabolism)
• Mice
• Neoplastic Stem Cells (drug effects)
• Phosphatidylinositol 3-Kinases (biosynthesis)
• Podophyllotoxin (administration & dosage, analogs & derivatives)
• Proto-Oncogene Proteins c-akt (biosynthesis)
• Receptor, IGF Type 1 (antagonists & inhibitors, biosynthesis)
• Signal Transduction (drug effects)
• Xenograft Model Antitumor Assays