Abstract
Hsp90 chaperone complexes are involved in maintaining the stability and signalling of Hsp90 client proteins such as the oestrogen receptor (ER). The ER is the primary mediator of breast cancer proliferation in response to oestrogen. Since increased ER levels and transcriptional activation are associated with over 50% of breast cancers, the ER is an attractive target for cancer treatment strategies. Hsp90 inhibitors such as 17AAG are known to destabilize these complexes by promoting proteasome-mediated degradation of the steroid hormone receptor leading to tumour growth inhibition [1] and sensitization to chemotherapy [2] and radiotherapy [3]. Using protein interaction assays, we have identified FKBPL, a novel gene that codes for an immunophilin-like protein, as an Hsp90 cochaperone associated with the ER and dynein motor protein complex. Overexpression studies have demonstrated that FKBPL modulates ER signalling and affects breast cancer growth and survival. Since most tumours become refractory to current hormonal therapies within a year of starting treatment, FKBPL represents a novel drug target that would enable the disruption of signalling pathways integral in maintaining ER-mediated tumour growth and survival.
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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