Abstract
Regulation of gene expression by the estrogen receptor (ER) requires the coordinated recruitment and dissociation of transcriptional coactivator complexes and concomitant chromatin remodelling and histone modification. In addition to the well-characterised recruitment of coactivator proteins, a number of corepressor proteins can also be recruited to the liganded ER, including RIP140 and L-CoR. We have recently identified a new ER interacting protein, ZNF366, which is recruited to the liganded ER, through interactions involving the zinc finger domains of both proteins. We show that repression of ER-regulated genes by ZNF366 involves recruitment of the well-described corepressor CtBP. This interaction is mediated by two sequence motifs in ZNF366, conforming to the consensus CtBP-binding motif (PXDLS). Mutation of these motifs in ZNF366 reduces, but does not abolish, the corepressor activity of ZNF366. Additionally, ZNF366 interacts with RIP140, raising the possibility that RIP140 and ZNF366 may act synergistically in regulating ER activity [1]. Finally, we show that although ZNF366 is expressed in normal breast epithelial cells, its expression is not detected in breast cancer cells. This raises the possibility that regulation of ER activity by ZNF366 may be important in breast cancer development.
Highlights
Obesity will soon be the leading preventable risk factor for many cancers
Previous epidemiological studies have investigated the relationship between individual nutrients such as vitamin D and O3 vitamin B12 and mammographic density, a strong marker of breast cancer risk [1], with varied results
We examine prospective data to determine A Bensmail, I Hutcheson, M Giles, J Gee, R Nicholson whether dietary patterns from childhood to adult life affect Tenovus Centre for Cancer Research, Welsh School of Pharmacy, mammographic density
Summary
Obesity will soon be the leading preventable risk factor for many cancers. The insulin-like growth factors (IGFs) have been strongly implicated as important risk factors for many epithelial cancers, including breast cancer, and for mediating the link between nutrition and these cancers. Overexpression of 15-PGDH partially restored sensitivity of TAMr cells to 4-hydroxytamoxifen by the MTT assay, demonstrating that 15-PGDH downregulation plays a functional role in the acquisition of TAMr. Treatment of TAMr MCF-7 cells with a DNA methyltransferase inhibitor (5-azacytidine), and a histone deacetylase inhibitor (trichostatin A), led to re-expression of 15-PGDH mRNA (by quantitative RT-PCR), suggesting that 15-PGDH is silenced via epigenetic mechanisms during the acquisition of TAMr. To address whether 15-PGDH downregulation is involved in clinical TAMr, we assembled a tissue microarray comprising 89 relapsed primary human breast cancers and 234 tamoxifen-sensitive controls. Oestrogen receptor-positive breast cancers develop resistance to anti-oestrogens by utilising alternative growth factor pathways as observed in our tamoxifen-resistant cell line (TAMR) These include EGFR, IGF1-R and Src signalling as well as increased growth and invasion. The tumour size was followed by regular measurement with calipers
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