In human they malignancies, increased circulating IGF 1 was associated with a greater risk of several cancers, including breast cancer. A crosstalk between IGF 1R and the Wnt pathway has been reported in colon cancer, oligo dendroglial cells, and chondrocytes. The inter action of these two pathways in breast cancer is intriguing and awaits further investigation. Recently, two reports demonstrated the essential role of IGF IGF 1R signaling in the maintenance of leukemia initiating cells in T cell acute lymphoblastic leukemia or in the transformation of hematopoietic progenitor cells in the mouse model of acute myelogenous leukemia. The IGF 1R expression of leukemia initiating cells in T cell acute lymphoblastic leukemia was maintained by Notch signaling, Inhibitors,Modulators,Libraries which also contributed to the mainte nance of BCSCs.

Whether the Notch pathway is involved in the IGF 1R signaling in BCSCs remains to be investigated. Inhibitors,Modulators,Libraries In solid tumors, chemoresistant colorec tal cells displayed a CSC phenotype and became more sensitive to IGF 1R inhibition. In hepatocellular carcinoma, Inhibitors,Modulators,Libraries the IGF 2 IGF 1R signal was shown to be involved in Nanog mediated self renewal of hepatic CSCs. These reports Inhibitors,Modulators,Libraries also support the importance of IGF 1R in CSC biology. In breast cancer, activation of the IGF 1R could result in stimulation of proliferation and metastasis through activation of insulin receptor substrate 1 and insulin receptor substrate 2. Furthermore, it has been reported that IGF 1R expres sion was positively correlated with a shorter disease free survival in triple negative breast cancer, the particu lar subtype with the highest rate of recurrence and higher percentage of BCSCs than other breast cancer subtypes.

In a recent report by Jones and collea gues, recurrence of breast Inhibitors,Modulators,Libraries cancer was observed in 16% of inducible IGF 1R transgenic mice upon the disconti nuation of doxycycline and the recurrence involved IGF 1R reactivation and IGF 1R independent mechanisms. Although the IGF 1R independent tumors dis played EMT phenotypes, their metastatic potential was things much lower than tumors with IGF 1R reactivation. Moreover, induction of EMT in immortalized human mammary epithelial cells by overexpressing EMT related transcriptional factors, twist or snail, or treatment with transforming growth factor b1 generated CD44 BCSCs. Recently, Lorenzatti and colleagues found that CCN6, a tumor inhibitory protein, could suppress the expression of EMT transcriptional factor ZEB1 in breast cancer cells through attenuation of IGF 1R signaling. Along this line, we also showed that inhibition of IGF 1R signaling suppressed the cell migration ability of CD44 BCSCs through induction of E cadherin, the adhesion molecule that blocks the EMT process, as well as suppression of other mesenchymal markers.