Use of proteomics for the early diagnosis fo breast cancer

Breast cancer mortality rates in The Netherlands are among the highest in Europe. To improve breast cancer survival, early detection is of vital importance. The introduction of the national breast cancer screening program has led to an improvement in stage distribution at diagnosis of breast cancer. But, for women for whom mammography is less effective, e.g. because of high density of the breast tissue, early detection techniques other than mammography would be very helpful. In the studies described in this thesis we searched for blood-based proteins that could indicate the presence of a breast tumor in an early stage. To this end, we first compared protein profiles in serum samples of symptomatic primary breast cancer patients and healthy women. We detected several proteins that showed statistically significantly higher or lower concentrations in breast cancer patients compared to healthy controls. In a study investigating pre-diagnostic serum samples, we found that two of these proteins, a 4.3 kDa fragment of inter-alpha trypsin inhibitor heavy chain H4 (ITIH4) and C3a des-arginine anaphylatoxin (C3adesArg) (8.9 kDa), were already increased in serum samples that were collected up to three years before the diagnosis of breast cancer. In a subsequent study we investigated the discriminative value of several peptides that were supposed to be generated by cancer specific exoproteases. Two of these peptides, amongst which a 2.4 kDa fragment of ITIH4, were found to be statistically significantly higher in breast cancer patients. After surgical removal of the tumor, concentrations of both peptides decreased to levels comparable to those in healthy controls. Asymptomatic breast lesions that are currently undetectable by mammographic screening may be detectable in the future using these potential breast cancer markers. Further studies are needed to confirm these results and to exclude false positive findings. The methods described in this thesis may also contribute to the detection of markers for monitoring progression of disease and response to therapy.