ellular processes , we in comparison blood insulin-stimulated gene expression towards the IGF-I – stimulated gene expression designs aacrjournals Cancer Res 7 November , Elesclom Downloaded from cancerres.aacrjournals on March 6, . American Association for Cancer Research towards the indicated remedies. Data are presented as mean tumor volume Search engine marketing. , P < 0.05 versus vehicle at each time point, -way ANOVA. B, IHC for total IGF- IR and P-InsR b Y46 /IGF-IR b Y3 . Left, representative images of tumors from A. Right, quantitative comparison of membrane histoscores H-score. , P < 0.000 , P < 0.05 versus vehicle, -way ANOVA. C, blood was collected via submandibular bleeding serum insulin was measured in duplicate. Data are presented as insulin levels SEM. , P < 0.05 versus vehicle , P < 0.05 versus OSI-906, t test. D, tumor-bearing mice were randomized to the indicated treatments as in A.
P < 0.05 versus vehicle , P < 0.05 versus OSI-906, -way ANOVA. q3d, every 3 days. Cisplatin reported by Creighton and colleagues, where MCF-7 cells were treated with IGF-I for 3 or 4 hours 33. Common intrinsic pathways and gene sets i.e., “metagenes” are coordinately modulated and tend to show better reproducibility and con- sistency than individual genes 34, 35. Therefore, we carried out gene set analysis GSA ref. 36 on each data set followed by hierarchical clustering of the gene set scores instead of indi- vidual genes to identify concordant/discordant transcriptional processes.
Similar to ndings reported by Loboda and collea- gues 37, we observed that insulin and IGF-I altered common gene sets following short-term treatment. In contrast, more distinct patterns were apparent after 4 hours Fig. 7B Sup- plementary Fig. S. Several gene sets enriched after 4 hours of IGF-I comprised cell-cycle – related pathways. In contrast, 4 hours of insulin enriched for gene sets comprising cell metab- olism, glycolysis, and Elesclomol 488832-69-5 pentose-phosphate pathway shunting. These data imply that IGF-IR and InsR elicit both common and distinct transcriptional outputs. 6780 Cancer Res 7 November , 0 Downloaded from cancerres.aacrjournals on March 6, 0 Copyright 0 American Association for Cancer Research Cancer Research Tumor volume mm 3 IGF-IR IGF-IR H-score Figure 6. Blockade of InsR/IGF-IR suppresses hormone-independent tumor growth. A, mice bearing MCF-7 xenografts of 50 mm or more were randomized 9 Published OnlineFirst September 9, 0 DOI:0.58/0008-547.CAN–95 Insulin/IGF-I Receptors and Antiestrogen Resistance Figure 7.
Insulin/IGF-I – induced gene expression correlates with patient outcome after endocrine buy Elesclomol therapy. MCF-7 cells were serum- starved for 4 hours, and then treated with or without 0 m g/mL insulin for 4 or 4 hours. RNA was isolated and analyzed by using gene expression microarrays. A, a tumor signature of insulin-induced gene expression correlates inversely with RFS in patients with t tamoxifen. B, genes altered by insulin or IGF-I stimulation were evaluated by GSA. Gene sets were grouped by hierarchical clustering and shown as a heatmap. C, an B Common/early gene sets UP Insulin-specific/late gene sets UP IGF-I-specific/late gene sets UP IGF-I-specific gene sets UP Insulin-specific/late gene sets DOWN Insulin-specific/early gene sets DOWN IGF-I-specific gene sets DOWN Common/early gene sets DOWN insulin/IGF-I gene expression signature predicts RFS in cohorts of patients with ER t breast cancer treated with tamoxifen. Published OnlineFirst September 9, 0 DOI:0.58/0008-547.CAN–95 Fox et al. Finally, we examined whether a common signature of genes regulated by both ligands was predictive of patient out- come. Similar processing of the published IGF-I data of health management system Creighton and colleagues 33 identi ed a common set of 55 genes altered by both ligands after short- or long-term treatment. The insulin/IGF-I gene signature correlated inversely with RFS in both cohorts of tamoxifen-treated pati- ents MDACC98 P
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