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

• Published in: Breast cancer research : BCR Vol. 15; no. 3; p. R39
• Main 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
• Format: Journal Article
• Language: English
• Published: London BioMed Central 12.05.2013; BioMed Central Ltd
• Subjects: Analysis; Animals; Biomedical and Life Sciences; Biomedicine; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cancer Research; Care and treatment; Cell Line, Tumor; Cell Proliferation - drug effects; Diagnosis; Female; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Genetic aspects; Humans; Insulin-Like Growth Factor I - genetics; Insulin-Like Growth Factor I - metabolism; Metastasis; Mice; Neoplastic Stem Cells - drug effects; Oncology; Phosphatidylinositol 3-Kinases - biosynthesis; Podophyllotoxin - administration & dosage; Podophyllotoxin - analogs & derivatives; Proto-Oncogene Proteins c-akt - biosynthesis; Receptor, IGF Type 1 - antagonists & inhibitors; Receptor, IGF Type 1 - biosynthesis; Research Article; Risk factors; Signal Transduction - drug effects; Stem cell research; Stem cells; Surgical Oncology; Transplantation; Xenograft Model Antitumor Assays; Taiwan; Rapamycin; Perifosine; Breast Cancer; ALDH Activity; BC0244 Cell
• ISSN: 1465-542X; 1465-5411; 1465-542X
• DOI: 10.1186/bcr3423

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-Akt Ser473 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.