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| Home > Publications database > M196R-TNFR2 and membrane TNFα down-regulate soluble TNFα-induced pro-metastatic functions in triple-negative breast cancer cells. |
| Home > Publications database > M196R-TNFR2 and membrane TNFα down-regulate soluble TNFα-induced pro-metastatic functions in triple-negative breast cancer cells. |
| Journal Article | DKFZ-2026-01699 |
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2026
BioMed Central
London
Abstract: Tumor necrosis factor α (TNFα) was connected to disease progression in breast cancer, through the activation of TNFR1 and, to some extent also of TNFR2, in cancer cells and/or in immune cells. We found that in triple-negative breast cancer (TNBC) patients, TNFR2 expression by the cancer cells was significantly connected to improved survival. By setting up an 8-cell system including TNBC cells infected to express combinations of TNFR1 with WT-TNFR2/TNFR2 variants, we determined cell responses to soluble TNFα (sTNFα), presented as recombinant human TNFα. We found that sTNFα-induced activation of TNFR1 gave rise to p65/p38 activation, elevated spontaneous tumor cell migration, greater directed invasion, and increased expression of pro-metastatic molecules (CXCL8, ICAM-1); lower levels of these functions were induced by sTNFα in WT-TNFR2-expressing cells. In TNFR1 knocked-out cells, the above sTNFα-induced functions were reduced by a M196R-SNP-TNFR2 variant (termed SNP-TNFR2). Also, the membrane form of TNFα (mTNFα) gave rise to a pronounced inhibition of sTNFα-induced p65 activation, tumor cell invasion, CXCL8 and ICAM1 expression in cells expressing TNFR1 + TNFR2 (WT-TNFR2/SNP-TNFR2), only TNFR2 (WT-TNFR2/SNP-TNFR2) and only TNFR1. In cells expressing only TNFR1, ERK1/2 activation was negatively correlated with sTNFα-induced p65 activation, and mTNFα expression has given rise to down-regulation of TNF receptor-associated factor 2 (TRAF2) expression alongside down-regulation of p65 activation. These findings provide novel insights into the roles of TNFR2 and mTNFα in cancer, suggesting that their potentially protective roles against tumor progression need be taken into account when TNFα-TNFR-directed therapies are considered in TNBC and in other malignancies as well.
Keyword(s): Breast cancer ; M196R-SNP-TNFR2 ; Membrane TNFα ; Soluble TNFα ; TNFR1 ; WT-TNFR2
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