TNF alpha Enhances Tamoxifen Sensitivity through Dissociation of ER alpha-p53-NCOR1 Complexes in ER alpha-Positive Breast Cancer

Abstract

Tamoxifen is widely used as a medication for estrogen receptor alpha (ER alpha)-positive breast cancer, despite the similar to 50% incidence of tamoxifen resistance. To overcome such resistance, combining tamoxifen with other agents is considered an effective approach. Here, through in vitro studies with ER-positive MCF7 cells and ER-negative MDA-MB-231 cells, validated by the use of xenograft mice, we investigated the potential of tumor necrosis factor alpha (TNF alpha) to enhance tamoxifen sensitivity and identified NCOR1 as a key downstream regulator. TNF alpha specifically degraded nuclear receptor corepressor 1 (NCOR1) in MCF7 cells. Moreover, knockdown of NCOR1, similar to TNF alpha treatment, suppressed cancer cell growth and promoted apoptosis only in MCF7 cells and MCF7 xenograft mice through the stabilization of p53, a tumor suppressor protein. Interestingly, NCOR1 knockdown with TNF alpha treatment increased the occupancy of p53 at the p21 promoter, while decreasing that of ER alpha. Notably, NCOR1 formed a complex with p53 and ER alpha, which was disrupted by TNF alpha. Finally, combinatorial treatment with tamoxifen, TNF alpha and short-hairpin (sh)-NCOR1 resulted in enhanced suppression of tumor growth in MCF7 xenograft mice compared to single tamoxifen treatment. In conclusion, TNF alpha promoted tamoxifen sensitivity through the dissociation of the ER alpha-p53-NCOR1 complex, pointing at NCOR1 as a putative therapeutic target for overcoming tamoxifen resistance in ER alpha-positive breast cancer.