Top-scoring gene networks, which are determined by ingenuity Pathways systems analysis of age and oxidative stress gene signatures in oestrogen receptor (ER)-positive breast cancers, commonly identify tumour necrosis factor (TNF) and transforming growth factor-β (TGFβ) pathway nodes. Ariadne Pathway studio was used to identify the respective TNF- and TGFβ- regulated (direct or indirect) targets from the 126-gene age signature (a) and the 62-gene oxidant–oestrogen+ER signature (intersection of oestrogen- and ER-regulated signature and oxidant-stressed signature; b). Regulatory directions were determined from primary references provided by Pathway studio, with positive (+) regulatory directions denoted by arrow-heads and negative regulatory directions denoted by bars (lines without either arrowheads or bars indicate ambiguous regulatory direction). Unigene symbols in red ovals indicate signature genes that are upregulated by oxidative stress or in early-onset breast cancer; those in green ovals indicate signature genes that are downregulated by oxidative stress or in early-onset breast cancer. At least 75% of the signature genes that have been shown to be regulated by TNF and TGFβ (a, b) contain nuclear factor κB (NFκB) or AP1 consensus element binding sites within their proximal promoters, as determined by EZRetrieve and TFSEARCH– (see TFSEARCH in Further information). ABCC3, ATP-binding cassette 3; ANG, angiogenin; AREG, amphiregulin; CDC2, cell division cycle 2; CLDN1, claudin 1; CTGF, connective tissue growth factor; CXCR4, chemokine (C-X-C motif) receptor 4; CXCL13, chemokine (C-X-C motif) ligand 13; CYP1A1, cytochrome P450 1A1; EGR1, early growth response 1; DAB2, disabled homologue 2; EFNA1, ephrin A1; ESR1, oestrogen receptor 1; GAL, galanin prepropeptide; IGFBP5, insulin-like growth factor binding protein 5; ITPR1, inositol 1,4,5-triphosphate receptor 1; KRT17, kera-tin 17; LAMC2, laminin-γ 2; LCN2, lipocalin 2; LEF1, lymphoid enhancer-binding factor 1; LRP2, low density lipoprotein-related protein 2; MMP9, matrix metalloproteinase 9; PLN, phospholamban; PLIN, perilipin; PTHLH, parathyroid hormone-like hormone; PTGES, prostaglandin E synthase; SERPINA1, serpin peptidase inhibitor 1; SOD3, superoxide dismutase 3; TAGLN, transgelin; TNC, tenascin C; TNFSF10, tumour necrosis factor (ligand) superfamily 10.
