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

Cancers

Sungmin Kwak¹  Ji-Hoon Jeong¹  Ji-Hye Song¹  Seung-Ho Park¹  Min-Jeong Kong¹  Hyunhee Kim¹  Kyung-Chul Choi¹  Gi-Jun Sung²  Hyo-Kyoung Choi³  Jangho Lee³  Jin-Taek Hwang³ 

[1] Asan Medical Center, Department of Biomedical Sciences, AMIST, University of Ulsan College of Medicine, Seoul 05505, Korea;Department of Obstetriccs, Gynecology and Reproductive Biology, Michigan State University, East Lansing, MI 49534, USA;Korea Food Research Institute, Wanju-gun 55365, Korea;

关键词: ER-positive breast cancer;    tamoxifen resistance;    TNFα;    NCOR1;   

DOI  :  10.3390/cancers13112601

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown