In this thesis mass spectrometry based protein profiling was applied as a new biomarker screening modality and it was evaluated whether or not this could be translated into early detection... Show more In this thesis mass spectrometry based protein profiling was applied as a new biomarker screening modality and it was evaluated whether or not this could be translated into early detection of breast cancer and pancreatic cancer. The status of breast cancer screening by proteomic profiling is discussed. Which steps have already been made? What is essential to implement this techniques in a clinical setting? Furthermore, the new protein profiling screening methods for pancreatic cancers are evaluated. Future studies will be suggested that are needed to translate this promising biomarker into a clinical application. Show less
Kool, M.; Sijp, J.R.M. van der; Kroep, J.R.; Liefers, G.J.; Jannink, I.; Guicherit, O.R.; ... ; Marang-van de Mheen, P.J. 2016
Breast cancer is the most common malignancy and the leading cause of cancer related death in women of the western world. For most women, increasing age is the primary risk factor for breast... Show more Breast cancer is the most common malignancy and the leading cause of cancer related death in women of the western world. For most women, increasing age is the primary risk factor for breast cancer. Therefore, the number of breast cancer patients is expected to further increase in the coming years. The work presented in this thesis is part of the collaborative FOCUS project, seeking insight into breast cancer disease (in the elderly), aiming to define normal tissue, breast cancer, and therapeutic sensitivity differences in observational, population-based cohorts consisting of elderly breast cancer patients. Topics discussed in this thesis are differences and clinical value of molecular differentiation, immune evasion, proliferative and apoptotic signaling; but also the predictive value of IGF1R and HER2 expression on the breast tumors. Last but not least, we discuss the effects of aging on tumorgenesis and the road to precision medicine. Only when all medical specialties bound to the care and cure of older cancer patients join forces, known as a multidisciplinary oncogeriatric battlefront, treatment goals, and implementation hereof will be achieved. Show less
Engels, C.C.; Kiderlen, M.; Bastiaannet, E.; Eijk, R. van; Mooyaart, A.; Smit, V.T.H.B.M.; ... ; Liefers, G.J. 2016
Adhesion G protein-coupled receptors (ADGRs) are believed to be activated by auto-proteolytic cleavage of their very large extracellular N-terminal domains normally acting as a negative regulator... Show moreAdhesion G protein-coupled receptors (ADGRs) are believed to be activated by auto-proteolytic cleavage of their very large extracellular N-terminal domains normally acting as a negative regulator of the intrinsically constitutively active seven transmembrane domain. ADGRG2 (or GPR64) which originally was described to be expressed in the epididymis and studied for its potential role in male fertility, is highly up-regulated in a number of carcinomas, including breast cancer. Here, we demonstrate that ADGRG2 is a functional receptor, which in transfected HEK293 cells signals with constitutive activity through the adhesion- and migration-related transcription factors serum response element (SRE) and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) presumably via coupling to Gα12/13 and Gαq. However, activation of these two pathways appears to occur through distinct molecular activation mechanisms as auto-proteolytic cleavage is essential for SRE activation but not required for NFκB signaling. The overall activation mechanism for ADGRG2 is clearly distinct from the established ADGR activation mechanism as it requires the large extracellular N-terminal domain for proper intracellular signal transduction. Knockdown of ADGRG2 by siRNA in the highly motile breast cancer cell lines Hs578T and MDA-MB-231 resulted in a strong reduction in cell adhesion and subsequent cell migration which was associated with a selective reduction in RelB, an NFκB family member. It is concluded that the adhesion GPCR ADGRG2 is critically involved in the adhesion and migration of certain breast cancer cells through mechanisms including a non-canonical NFkB pathway and that ADGRG2 could be a target for treatment of certain types of cancer. Show less
Bulten, B.F.; Verberne, H.J.; Bellersen, L.; Oyen, W.J.G.; Sabate-Llobera, A.; Mavinkurve-Groothuis, A.M.C.; ... ; Geus-Oei, L.F. de 2015
Selection of patients who will likely respond or will develop relevant side effects has the potential to improve anticancer therapy. Considering the many contributing factors in drug disposition,... Show moreSelection of patients who will likely respond or will develop relevant side effects has the potential to improve anticancer therapy. Considering the many contributing factors in drug disposition, we hypothesized that variability in drug disposition could be better explained by phenotype, rather than by the genotype alone. In this thesis, phenotype tests in oncology were studied, with a focus on phenotype breath tests and CYP2D6 metabolism in breast cancer patients using tamoxifen. A review is given of phenotype studies published before 2011 addressing drug metabolizing enzymes in relation to anticancer drugs. The 13C-dextromethorphan-breath test was related to CYP2D6 genotype and serum concentrations of endoxifen, the active metabolite of tamoxifen. A 13C-dextromethorphan breath test was equally predictive of endoxifen levels as compared to the CYP2D6 genotype. We showed that there was no difference in CYP2D6 phenotype between metastasized patients and early breast cancer patients. Because endoxifen levels did not significantly differ between the two groups as well, our findings do not have clinical implications thus far. Show less
This thesis was divided in two parts. Part I demonstrated benefit of zoledronic acid addition to chemotherapy in terms of pathological response in postmenopausal women. Part II is all about... Show moreThis thesis was divided in two parts. Part I demonstrated benefit of zoledronic acid addition to chemotherapy in terms of pathological response in postmenopausal women. Part II is all about neoadjuvant endocrine therapy, and discusses the optimal duration of this treatment and the information on treatment efficacy that aromatase-inhibitor specific adverse events may provide. Show less