Determining whether there are gene amplifications or losses in tumours resistant to tamoxifen (and subsequently aromatase inhibitors) and thereby identify novel putative resistance genes.

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Recently aCGH has begun to be exploited since this provides high resolution in a mapped fasion across the genome.

Recently aCGH has begun to be exploited since this provides high resolution in a mapped fasion across the genome.Somatic gene loss and amplification are characteristics of cancer development. Patterns of loss and gain are closely associated with conventional pathological features of breast cancer. Grade and ER status, more than any other clinico-pathological feature, are strongly associated with the number and, most importantly, the pattern of unbalanced genomic abnormalities in breast cancer cells.

The de novo resistance of certain cancers to specific therapies has also been associated with losses/gains, particularly in ovarian cancer. HER2 amplification is perhaps the best characterised genetic aberration associated with tamoxifen resistance in breast cancer, although even here the evidence has been unclear, in part because of the low proportion of ER+ tumours that are also HER2+, but also because of differing methodology that has been based on numerous immunohistochemical approaches as opposed to assessing the DNA change itself

It is therefore possible that further DNA aberrations exist which are associated with resistance to tamoxifen and may be either mechanistically involved or useful biomarkers of resistance or both.

CGH is a favoured method for the identification of losses and gains of DNA in tumour tissue. Recently array CGH (aCGH) has begun to be exploited since this provides high resolution in a mapped fashion across the genome. We will apply this technique to DNA extracted from the tumours of patients with assessable tamoxifen-treated breast cancer to investigate DNA aberrations.

Findings with statistical significance will be further investigated using other translational resources and/or functional analyses in cell lines as deemed appropriate. We will also conduct subsequent analyses to assess whether these genetic aberrations extend to resistance to AIs.