In:
Cancers, MDPI AG, Vol. 13, No. 11 ( 2021-05-26), p. 2601-
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
2072-6694
DOI:
10.3390/cancers13112601
Language:
English
Publisher:
MDPI AG
Publication Date:
2021
detail.hit.zdb_id:
2527080-1
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