Background: The growth hormone/ IGF-I axis is important in the pathogenesis of breast cancer and increased IGF-I signalling through the IGF-I receptor (IGF-IR) has been implicated in the development of tamoxifen resistance in breast cancer.
Aims: To compare mRNA and protein expression of IGF-I & IGF-IR in (i) wild type (WT) and tamoxifen resistant (TR) MCF-7 breast cancer cells and (ii) breast cancer tissue from women with primary and recurrent, tamoxifen resistant breast cancer.
Methods: (i) We have already established a TR cell line from previously obtained WT MCF-7 breast cancer cells (ATCC). RNA was extracted from the cells and mRNA levels assessed using quantitative real time (Taqman) RT-PCR. Western blotting for the IGF-IRß was carried out using standard protocols. (ii) Specimens of breast cancer were obtained at time of surgery from women with primary and TR breast cancer (informed consent was obtained and local regional ethical approval has been granted). Quantitative real time PCR was performed as above. mRNA levels are expressed as copy number per microgram total RNA and are the mean of 10 samples.
Results: (i) Neither WT or TR MCF-7 cells express IGF-I. IGF-IR mRNA is significantly decreased in TR (3.60E+07) compared to WT cells (2.76E+08) (P<0.001). There was no significant difference in mRNA levels of either IGF-II (TR 2.59E+05 vs. WT 6.87E+05) or IGFBP-3 (TR 2.72E+08 vs. WT 3.16E+08). Western blotting confirms reduced IGF-IR protein levels in TR compared to WT cells. (ii) IGF-I (TR 9.9E+05 vs. WT 1.1E+07) and IGF-IR (TR 1.34E+05 vs. WT 1.28E+06) levels are significantly reduced in tamoxifen resistant compared to primary cancers (P<0.0001). There is no significant difference in either IGF-II or IGFBP3 expression between the two groups.
Conclusion: Development of tamoxifen resistance both in vivo and in vitro is associated with decreased expression of IGF-I signalling components.