Annals of Oncology 15:885-890, 2004
© 2004 European Society for Medical Oncology
Original Paper |
NF-
B inhibition markedly enhances sensitivity of resistant breast cancer tumor cells to tamoxifen
Received 7 January 2004; revised 17 February 2004; accepted 18 February 2004
Studies show that high Akt activity in breast carcinoma is associated with endocrine therapy resistance. Breast cancer cell lines expressing a constitutively active Akt are able to proliferate under reduced estrogen conditions, and are resistant to the growth inhibitory effects of tamoxifen. Understanding the targets of Akt signaling mediating tamoxifen resistance is of clinical significance. One possible target is nuclear factor kappa B (NF-
B), a transcription factor that plays a critical role in resistance to apoptosis and the induction of angiogenesis and invasion. In the present study, we found that Akt activity correlated with phosphorylation of IB (the negative regulator of NF-B), NF-B DNA binding and tamoxifen resistance in vivo. Importantly, we found that co-treatment with the NF-B inhibitor, parthenolide, or overexpression of IB superrepressor restored tamoxifen sensitivity to our refractory Akt MCF-7 cells. These data suggest that activation of NF-B via the PI3K/Akt signaling pathway may be a significant mechanism for development of endocrine therapy resistance in breast cancer, and that inhibition of NF-B may be an effective treatment strategy to limit the progression of this disease.
1 Department of Medicine, UT Health Science Center at San Antonio, San Antonio, TX; 2 The Johns Hopkins Oncology Center, Johns Hopkins Medical Center, Baltimore, MD, USA
Key words:
Akt, breast cancer, NF-B, tamoxifen resistance
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