NF-κB inhibition markedly enhances sensitivity of resistant breast cancer tumor cells to tamoxifen

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-kappaB), 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 IkappaB (the negative regulator of NF-kappaB), NF-kappaB DNA binding and tamoxifen resistance in vivo. Importantly, we found that co-treatment with the NF-kappaB inhibitor, parthenolide, or overexpression of IkappaB superrepressor restored tamoxifen sensitivity to our refractory Akt MCF-7 cells. These data suggest that activation of NF-kappaB 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-kappaB may be an effective treatment strategy to limit the progression of this disease.