Type-I Insulin-Like Growth Factor Receptor (IGF1R)-Estrogen Receptor (ER) Crosstalk Contributes to Antiestrogen Therapy Resistance in Breast Cancer Cells
Annual rept. 1 Feb 2010 - 31 Jan 2013
MINNESOTA UNIV MINNEAPOLIS
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Tamoxifen, the first targeted therapy, has shown great success in treating estrogen receptor ER positive breast cancer. However, both acquired and de novo resistance to this therapy prevents it from being effective in all situations. Multiple lines of evidence indicate that increased signaling through growth factor pathways, such as the IGF pathway, mediates resistance to tamoxifen. The link between ER and ICGF1R leads us to hypothesize that IGF system crosstalk with the ER contributes to tamoxifen resistance. Tamoxifen resistance has thus provided researchers with a reason to investigate other growth factor pathways involved in breast cancer. As new targeted therapies are being developed, it will be important to examine their benefit with existing therapies. In order to examine the effectiveness of anti-IGF1R inhibitors in vitro, tamoxifen resistant TamR cells were generated by culturing MCF-7L and T47D cells in the presence of 4-OH-tamoxifen for 6 months. TamR cells had dimished levels of IGF1R, with unchanged levels of insulin receptor IR. Further, TamR cells failed to respond to IGF-I induced p-AKT activation, while retaining responsiveness to both insulin and IGF-II. Additionally, IGF-I failed to enhance the proliferation and anchorage-independent growth of TamR cells however, both insulin and IGF-II were able to enhance proliferation in MCF anchorage-independent growth. An IGF1R antibody was effective in inhibiting signaling, anchorage-independent growth, and proliferation in MCF-7L cells, but had no effect in TamR cells. In contract, an IGF1RTR tyrosine kinase inhibitor was effective in both MCF-7L and TamR cells. In a xenograft model, an IGF1R antibody was able to inhibit estrogen stimulated tumor growth, but had no additive effect when combined with tamoxifen treatment. Further, tamoxifen-treated xenografts had diminished IGF1R levels.
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