Abstract
Protease genes are involved in multiple steps of cancer progression, including cell growth, migration and angiogenesis. These genes are valuable as prognostic and/or diagnostic markers of disease and are potential therapeutic targets. We used TaqMan® real-time quantitative PCR to conduct the first detailed quantitative expression profiling of the entire family of metalloprotease and serine protease genes and their inhibitors in breast cancer (over 380 genes). Using a bank of 60 samples (50 cancer and 10 normal mammary tissue) collected at the Norfolk and Norwich University Hospital [1] we have identified a number of genes that show significant disregulation in tumour samples compared with normal breast tissue. Expression correlates either positively or negatively with tumour grade in many genes. A further cohort of 229 Dutch patients with more extensive clinical history [2] was profiled in a subset of the metalloproteinase genes. Among the genes that showed significant aberrant expression, Matrix metalloproteinase-8 (MMP8) emerged as a candidate to play a protective role during tumour progression. MMP8 was found to have significant prognostic value and was strongly correlated with prolonged survival. MMP8 is prognostic as a continuous variable for relapse-free survival (hazard ratio = 0.76, P = 0.045) and for overall survival (hazard ratio = 0.69, P = 0.025). Expression of MMP8 also correlated with lymph node involvement, reduced expression equating to greater nodal spread (P = 0.001). Expression of MMP8 was independent of tumour grade. These data show that MMP8 is prognostic in breast cancer, and suggest that the function of MMP8 antagonizes metastasis.
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 have demonstrated that this paradigm applies to mammary epithelial cells, which undergo a switch from Th1 to Th2 cytokine production upon the induction of differentiation
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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