Summary
Breast cancer is a very heterogeneous disease, consisting of different molecular subtypes. Effective, targeted treatment is available for estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) positive tumors. However, ~15% of breast tumors are negative for ER, HER2 and progesterone receptor (PgR), the so-called triple negative subtype. Women with triple negative breast cancer have the worst prognosis, due to the aggressive nature of these tumors and current absence of suitable targets for therapy. Evidently, identification of appropriate prognostic protein targets for this group of patients is of vital importance.
We therefore aim to identify protein markers specific for the triple negative subgroup, by performing comparative proteomics profiling. Our proposed study covers a biomarker discovery phase, validation phase and a subsequent functional proteomics phase. For discovery studies, we have available 150 fresh frozen triple negative breast tumors, of which 50 presented with distant metastasis within 5 years. Protein markers associating with distant metastasis will be identified using high-performance FT-based mass spectrometry in combination with label-free quantification. Putative differentially abundant proteins will be validated in an independent sample set through quantitative multiple-reaction monitoring on a triple quadrupole mass spectrometer. In the final phase, pathway analysis on validated markers will be performed and key proteins will be studied for their functional role in triple negative breast cancer. Using a wide variety of breast cancer cell lines, we will study the effect of over-expression or silencing of key proteins on breast cancer cell growth and survival, apoptosis, migration, and invasion.