Novo Nordisk Fonden - Molecular mechanisms of estrogen receptor function in endocrine resistant and metastatic breast cancer

Breast cancer is the most common type of cancer affecting women with around 4,500 new cases every year in Denmark. Most breast cancers (~75%) express the estrogen receptor (ER), which has recently been implicated in the progression of the disease. Genomics analyses of human tumour samples revealed that ER binding to chromatin is reprogrammed (i.e. ER binds many new sites and is lost at others) in poor outcome and metastatic tumours compared to good outcome tumours. Importantly, this reprogramming of ER binding correlates with altered gene expression that is linked to poor prognosis for the patient, suggesting that ER reprogramming drives disease progression. Here we aim to delineate the mechanisms controlling reprogramming of ER binding and function in endocrine-resistant and metastatic tumours, which may provide new clinical opportunities. First, we will investigate if cytokine signaling, which has previously been implicated in cancer metastasis, drives ER reprogramming in advanced stages of the disease. This will be done using state-of-the-art genomics techniques. Second, we will employ a newly developed proteomics approach (RIME) to identify novel regulators of ER in endocrine-resistant and metastatic cancer cells in an unbiased manner. Using RIME, we will also identify proteins that selectively bind to ER mutants, which have recently been identified specifically in endocrine-resistant metastatic breast cancers. The impact of these novel ER regulators on ER reprogramming and disease progression will be investigated using genomics approaches as described above. Endocrine-sensitive and -resistant cell lines will be widely used for these studies, but we will also make extensive use of patient-derived tumour explants and xenografts to ensure our findings have clinical relevance. Taken together, these studies will provide important new molecular insight into the etiology of endocrine-resistance and metastasis in breast cancer and may reveal new potential drug targets.