TNFα Enhances Tamoxifen Sensitivity through Dissociation of ERα-p53-NCOR1 Complexes in ERα-Positive Breast Cancer.

Abstract

Simple SummaryTamoxifen has been clinically applied as a central chemotherapeutic agent for treatment of estrogen receptor (ER)-positive breast cancer. However, many ER-positive breast cancer patients with the high ER level demonstrate intrinsic resistance against the tamoxifen therapy. The aim of our study was to find an effective approach to enhance tamoxifen sensitivity. We found that tumor necrosis factor α (TNFα) has a potential to overcome tamoxifen resistance through disruption of nuclear receptor corepressor 1 (NCOR1)-p53-ERα complexes in ER-positive MCF7 xenograft mice. NCOR1 knock-down with TNFα treatment induced ERα destabilization and increased the occupancy of p53 at the p21 promoter. Finally, we confirmed the combinational application with tamoxifen, TNFα and short-hairpin NCOR1 showed the enhanced suppressive effect of tumor growth in MCF xenograft mice compared to single tamoxifen treatment. These results provide a possibility for application of NCOR1 as a putative therapeutic target to overcome tamoxifen resistance in ERα-positive breast cancer.Tamoxifen is widely used as a medication for estrogen receptor α (ERα)-positive breast cancer, despite the ~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 α (TNFα) to enhance tamoxifen sensitivity and identified NCOR1 as a key downstream regulator. TNFα specifically degraded nuclear receptor corepressor 1 (NCOR1) in MCF7 cells. Moreover, knockdown of NCOR1, similar to TNFα 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 TNFα treatment increased the occupancy of p53 at the p21 promoter, while decreasing that of ERα. Notably, NCOR1 formed a complex with p53 and ERα, which was disrupted by TNFα. Finally, combinatorial treatment with tamoxifen, TNFα and short–hairpin (sh)-NCOR1 resulted in enhanced suppression of tumor growth in MCF7 xenograft mice compared to single tamoxifen treatment. In conclusion, TNFα promoted tamoxifen sensitivity through the dissociation of the ERα-p53-NCOR1 complex, pointing at NCOR1 as a putative therapeutic target for overcoming tamoxifen resistance in ERα-positive breast cancer.