Phosphorylation of ER? and HIF-1? in breast cancer with focus on tamoxifen response and links to kinase activation
Anti-oestrogens are commonly used in adjuvant breast cancer treatment and for a long time tamoxifen has been the main endocrine treatment. Patients who are eligibly for endocrine treatment are selected by the tumour-specific expression of oestrogen receptor (ER) and approximately 70 % of all breast cancer patients are classified as ER positive. However, resistance to tamoxifen is common and several patients will experience tumour relapse and might also die from their disease. This stresses the need for identifying treatment predictive factors that can guide clinicians during treatment decisions. We have identified biomarkers that were associated with tamoxifen response in a material of premenopausal breast tumours. One of the markers is Pak1, a serine/threonine protein kinase, of which high expression and particular nuclear localisation was associated with poor tamoxifen response. Two other biomarkers are different ER phosphorylations at serine 305 and serine 118; ERS305-P and ERS118-P, respectively. Tumours that were positive for ERS305 were associated with poor tamoxifen response while tumours with high expression of ERS-118 were associated with a good response. Furthermore, we have studied associations between the activated kinases responsible for these ER phosphorylations and tamoxifen response. Our observations led us to conclude that ERS118-P and ERS305-P are better tamoxifen predictive factors than their respective phosphorylating kinases, and possibly, using a combination of the phosphorylations might be even more valuable in predicting the response. In addition, we have identified Pak1 as a regulator of the hypoxic response in breast cancer cells. More specifically, we have observed Pak1-mediated phosphorylation of the hypoxia inducible transcription factor 1? (HIF-1?). Silencing of Pak1 led to decreased HIF-1? levels and less transcriptional activity, suggesting that Pak1 phosphorylation stabilises HIF-1? and thereby increases HIF-1?’s ability to induce gene expression during tumour hypoxia.
Source Type:Doctoral Dissertation
Date of Publication:01/01/2009