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Loss of tumor necrosis factor superfamily genes in breast cancer cell lines (1047.8)
Author(s) -
Hunter Dylan,
Edson Leanne,
Coleman William
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.1047.8
Subject(s) - demethylating agent , cancer research , dna methylation , gene silencing , biology , tumor necrosis factor alpha , cancer cell , cancer , epigenetics , immunology , gene , gene expression , genetics
A subset of human triple‐negative breast cancer cell lines exhibit aberrant DNA hypermethylation that is associated with DNA methyltransferase hyperactivity, overexpression of DNMT3b, and methylation‐dependent silencing of numerous genes. These breast cancer cell lines are resistant to standard chemotherapeutic agents, but can be sensitized to chemotherapy with demethylating drugs (5aza). In this study, we surveyed expression of 328 genes associated with apoptosis and survival in Hs578T cells using BioRad Prime PCR Pathway Plates. This analysis identified several members of the tumor necrosis factor (TNF) and TNF receptor superfamilies that are not expressed (undetected) or expressed at negligible levels in Hs578T cells, including TNFSF8, TNFSF10, TNFSF11, TNFSF14, TNFSF15, TNFRSF13B, TNFRSF17, and TNFRSF18. Among these TNF/TNFR superfamily genes, TNFSF10, TNFSF14, TNFSF15, TNFRSF1B, and TNFRSF8 have been directly implicated as activators of apoptosis. Epigenetic silencing of these genes (directly or indirectly) would convey a survival advantage to the cancer cells through elimination of pro‐apoptotic signaling. TNFSF10, TNFRSF1B, and TNFRSF8 have been shown to be subject to methylation‐dependent silencing in cancer cells. The contributions of aberrant DNA hypermethylation to the silencing of pro‐apoptotic genes in the TNF/TNFR superfamilies as a mechanism of chemotherapeutic resistance was explored further using a panel of breast cancer cell lines. The results suggest that treatment of triple‐negative breast cancer cell lines that display aberrant DNA hypermethylation with demethylating agents (like 5aza) sensitizes them to standard chemotherapeutic drugs (Doxorubicin, Paclitaxel, 5‐fluorouracil) by reactivation of pro‐apoptotic genes in the TNF/TNFR superfamilies. This experimental observation forms the basis for designing new treatment approaches for patients with triple‐negative breast cancer that combine epigenetic and cytotoxic drugs.