Abstract
Insulin-like growth factor binding protein 3 (IGFBP-3) is the most abundant insulin-like growth factor binding protein in human serum and is able to modulate cell proliferation independently of its ability to bind insulin-like growth factor. Tumour-associated increases in IGFBP-3 levels relate to upregulation of epidermal growth factor receptor (EGFR) and HER-2 with increasing oestrogen independence. Remodelling of the extra-cellular matrix with increased fibronectin expression in poor prognostic tumours further enhances EGFR levels and signalling.
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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