P2-01-03: Insulin-Like Growth Factor I (IGF) Induced Metastasis Signature Correlates with Poor Prognosis and Decreased Distant Metastasis-Free Survival in Human Breast Cancer.
Authors: D Sachdev, AL Sarver
Journal: Cancer Research (2011)

Abstract The insulin-like growth factors (IGFs) acting via the type I insulin-like growth factor receptor (IGF-1R) regulate tumor growth, survival and metastasis of multiple types of cancers. Agents targeting IGF-1R are currently being tested in phase II/III clinical trials in human cancers. We have previously reported that IGF1R can regulate metastasis independently of primary tumor growth in a model of high risk metastatic breast cancer using the triple negative MDA435/LCC6 metastatic cancer cells, which form spontaneous lung metastases when injected into the mammary fat pad of mice. We have shown that disruption of IGF signaling either with an antibody against IGF1R, AVE1642, or a dominant negative IGF-1R construct, does not affect growth in the mammary fat pad but inhibits pulmonary metastases and colonization of the lungs. Regulation of such a phenotype will not be measured in clinical trials and these findings imply that clinical trials of this therapeutic strategy may need to adjust their endpoints for assessing benefit by taking into account that inhibition of IGF1R signaling may inhibit metastasis but not primary tumor growth. Here, we sought to develop an IGF induced metastasis signature that may be useful in selecting patients that could benefit from IGF1R targeted therapy and determine if changes in expression of the genes in the signature can be useful in monitoring response. Serum starved LCC6-WT cells (with wild-type functional IGF1R) and LCC6-DN (cells with dominant negative IGF1R) were treated with IGF-I, AVE1642 (fully human antibody against IGF1R that inhibits metastasis but not tumor growth in the mammary fat pad), or AVE1642+ IGF-I for 4 and 24 hours and microarray analysis was performed using the U133 Plus 2.0 human arrays with 47,000 transcripts. IGF-I regulated over 100 transcripts in LCC6-WT cells compared to IGF-I in LCC6-DN cells. Over 400 transcripts were basally differentially expressed in LCC6-WT cells compared to LCC6-DN cells. Array data were also analyzed to determine genes regulated by IGF-I signaling in LCC6-WT cells compared to untreated LCC6-WT cells and if disruption of signaling with AVE1642 affected genes whose expression was regulated by IGF-I signaling. A total of 263 transcripts were regulated by IGF signaling in LCC6-WT cells compared to untreated cells and AVE1642 treatment reversed the regulation of all transcripts induced by IGF-I in LCC6-WT cells. 53 of the most significantly regulated genes were used to query two different human breast tumor datasets to determine if genes in IGF signaling induced metastasis signature are associated with lymph node metastasis and poor prognosis in human tumors. IGF regulated metastasis signature genes were expressed in human tumors in the van't Veer and Wang datasets. Further, IGF activated metastasis signature was correlated to decreased survival and decreased distant metastasis free survival in breast cancer patients. Our results suggest that presence of IGF induced metastasis signature in patients confers prognostic value and identifying IGF driven metastasis signatures may be useful to identify and monitor patients who could benefit from IGF1R targeted therapy for inhibition of metastatic disease. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-01-03.