Klinisk institutt 2

Midtveisevaluering - Olivera Bozickovic



Metabolic switch in oestrogen-dependent breast cancer

A majority of breast cancers (70%) express oestrogen receptor alpha (ERa), a molecular driver of cell growth and proliferation. This transcription factor is a member of the class I nuclear receptor family (steroid receptor). The transcriptional activity of ERa is regulated by the binding of its ligand 17β-oestradioland and the recruitment of coactivators or corepressors to the transcriptional complex.

Steroid receptor coactivator 2 (SRC-2) is a classical ERa coactivator. Unlike other members of the SRC coactivator family, SRC-2 may also have a repressive potential on ERa transcription. SRC-2 is downregulated by protein degradation via the cAMP/PKA pathway. Based on studies we found, two functionally independent protein domains are involved in SRC-2 degradation (Hoang et al 2013). We used one of the domains, aa 347-758, as bait in a yeast two-hybrid assay to identify proteins that may interact with SRC-2. Cyclin C (CCNC) was identified as the only reliable interacting partner. Moreover, protein level of SRC-2 depends on the CCNC level, suggesting that SRC-2 is involved in cell cycle regulation. Further investigation into SRC-2-responsive cell cycle genes and the nature of these genes suggests CCNC-SRC-2 interaction is involved in the control of G1/S transition.

Function of ERa in breast cancer is as diverse as are its interacting coregulators. One of these is a metabolic regulator peroxisome proliferative activated receptor gamma coactivator 1 alpha (PGC-1a), most known for stimulating biogenesis of mitochondria. Our research group has detected increased level of PGC1a in patients responding to aromatase inhibitor therapy (Flågeng MH 2009). Changes in the intracellular metabolism due to therapy on the breast cancer are still under investigation. Most likely, these changes can be attributed to metabolic reprogramming, whereby tumour cells respond to therapy by switching from glycolysis to oxidative phosphorylation as the major energy producing pathway. The project encompasses clinical analysis of tumour samples before and after treatment with the aromatase inhibitor exemestrane, using next-generation RNA sequencing, and in vitro analysis of changes in gene expression, of metabolic pathways, mitochondrial abundance and activity.