Disease recurrence is a common problem in breast cancer and yet the mechanisms enabling tumour cells to evade therapy and colonise distant organs remain unclear. We sought to characterise global expression changes occurring with metastatic disease progression in the endocrine resistant setting. Here, for the first time, RNAsequencing has been performed on matched primary, nodal and liver metastatic tumours from tamoxifen-treated patients following disease progression. Expression of genes commonly elevated in the metastases of sequenced patients was subsequently examined in an extended matched patient cohort with metastatic disease from multiple sites. The impact of tamoxifen treatment on endocrine resistant tumours in vivo was investigated in a xenograft model. The extent of patient heterogeneity at the gene level was striking. Less than 3% of the genes differentially expressed between sequential tumours were common to all patients. Larger divergence was observed between primary and liver tumours than between primary and nodal tumours, reflecting both the latency to disease progression and the genetic impact of intervening therapy. Furthermore, an endocrine-resistant in vivo mouse model demonstrated that tamoxifen treatment has the potential to drive disease progression and establish distant metastatic disease. Common functional pathways altered during metastatic, endocrine-resistant progression included extracellular matrix receptor interactions and focal adhesions. This novel global analysis highlights the influence of primary tumour biology in determining the transcriptomic profile of metastatic tumours, as well as the need for adaptations in cell-cell communications to facilitate successful tumour cell colonisation of distant host organs.
Royal College of Surgeons in Ireland ->