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

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.

Effects of conceptus proteins on endometrium and blood leukocytes of dairy cattle using transcriptome and meta-analysis

“…Additionally, analysis for causal networks predicted that IFNT3 may restrict nuclear receptor corepressor 1 (NCOR1) signaling leading to inhibition of early pregnancy loss. NCOR1 repress transcription of nuclear receptors such as ESR1 (Kim et al, 2021), RAR (Horlein et al, 1995), PPARG (Battaglia et al, 2010) and IRF7 (Ahad et al, 2020) by recruiting and activating histone deacetylases (HDAC) that generate a closed conformation of the chromatin. In the bovine endometrium, NCOR1 protein expression was greater on day 6-16 of the estrous cycle and positively correlated with P4 concentration (Rekawiecki et al, 2017).…”

Estrogen Receptor Signaling in Breast Cancer

“…The loss of NCOR1 results in accelerating the development of breast cancer, and a decrease in its expression may be the result of acquiring resistance to tamoxifen [127,128]. Additionally, it has been shown that the association of NCOR1 with other corepressors such as SAFB1 (scaffold attachment factor B 1) and SAFB2 (scaffold attachment factor B 2) reduces the expression of ERα [129,130]. Recently, Aylon and colleagues reported [131] that NCOR1 repressive activity is enhanced by LAST1 (large tumor suppressor 1) and proposed that this axis may restrict breast cancer progression.…”