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- W2964452386 abstract "e13590 Background: Crosstalk between the insulin-like growth factor (IGF) and estrogen receptor (ER) systems has been well defined in breast cancer. The majority of anti-IGF1R clinical trials are in estrogen receptor-positive patients who have progressed on prior endocrine therapy; early reports show no benefit for addition of IGF1R inhibitors to endocrine therapy in this setting. Methods: To examine the effectiveness of IGF1R inhibitors, tamoxifen-resistant (TamR) cells were generated in MCF-7L and T47D cells. IGF1R was inhibited by monoclonal antibody (dalotuzumab) or IGF1R/insulin receptor (IR) tyrosine kinase inhibitor (AEW541). Results: TamR cells had diminished levels of IGF1R with unchanged levels of IR. Further, TamR cells failed to respond to IGF-I-induced Akt activation, proliferation, and anchorage-independent growth while retaining responsiveness to both insulin and IGF-II. Dalotuzumab inhibited IGF-I-mediated Akt phosphorylation, proliferation, and anchorage-independent growth in parental cells, but had no effect on TamR cells. AEW541 with equal potency for the IGF1R and IR, inhibited IGF-I-, IGF-II-, and insulin-stimulated Akt phosphorylation, proliferation, and anchorage-independent growth in parental cells. Interestingly, AEW541 also inhibited insulin- and IGF-II-stimulated effects in TamR cells. MCF-7L xenografts from estrogen replete mice were inhibited by dalotuzumab. However, dalotuzumab add no additional benefit to tamoxifen in estrogen depleted mice. Xenograft tumors from tamoxifen treated mice had reduced levels of IGF1R mRNA. Conclusions: Because ER regulates IGF1R mRNA expression, inhibition of IGF1R does not add to tamoxifen growth inhibition of breast cancer cells. Furthermore, inhibition of IR may be necessary to manage tamoxifen resistant breast cancer. The failure of clinical trials of IGF1R inhibitors in endocrine resistant breast cancer could be explained by this crosstalk between the two growth regulatory receptors." @default.
- W2964452386 created "2019-08-13" @default.
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- W2964452386 date "2012-05-20" @default.
- W2964452386 modified "2023-09-27" @default.
- W2964452386 title "Expression of type I insulin-like growth factor receptor (IGF1R) in tamoxifen-resistant cells: Implications for cotargeting of IGF1R and estrogen receptor (ER) in breast cancer." @default.
- W2964452386 doi "https://doi.org/10.1200/jco.2012.30.15_suppl.e13590" @default.
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