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
Kaptein, A.A.; Schoones, J.W.; Fischer, M.J.; Thong, M.S.Y.; Kroep, J.R.; Hoeven, K.J.M. van der 2015
Women with breast cancer respond to the illness and its medical management in their own personal way. Their coping behavior and self-management are determined by their views (cognitions) and... Show moreWomen with breast cancer respond to the illness and its medical management in their own personal way. Their coping behavior and self-management are determined by their views (cognitions) and feelings (emotions) about symptoms and illness: their illness perceptions. This paper reports the results of a systematic literature review of illness perceptions and breast cancer. In the 12 studies identified, published between 2012 and 2015, illness perceptions were found to be important concomitants of medical and behavioral outcomes: fear of recurrence, distress, quality of life, satisfaction with medical care, use of traditional healers, and risk perception. Intervention studies are called for where the effects are examined of replacing unhelpful illness perceptions by more constructive ones. Health care providers do well by incorporating illness perceptions in their care for women with breast cancer, as this is instrumental in improving patients' quality of life. Show less
Kiderlen, M.; Ponti, A.; Tomatis, M.; Boelens, P.G.; Bastiaannet, E.; Wilson, R.; ... ; EusomaDB Working Grp 2015
There is epidemiological evidence that the use of some insulin analogues by diabetic patients is correlated with an increased cancer risk. In vitro exposure experiments revealed that insulin... Show moreThere is epidemiological evidence that the use of some insulin analogues by diabetic patients is correlated with an increased cancer risk. In vitro exposure experiments revealed that insulin glargine (LANTUS) was the only commercial insulin analogue with an increased mitogenic potential. In the human body the injected insulin glargine is rapidly degraded into two main metabolites with a metabolic activity. These two compounds have a mitogenic potential that was not increased compared to regular insulin. Gene expression analysis on a stimulated MCF7-based cell line panel showed that the insulin-like growth factor 1 (IGF1) receptor was the main receptor involved in the insulin analogue induced mitogenic signaling. A chronic exposure experiment with the humanized p53R270H+/-WAPCre mouse model revealed that none of the commercially available insulin analogues induced mammary gland tumor multiplicity or decreased the tumor latency time. However, a follow-up whole transcriptome analysis indicated that some tumors in the insulin glargine treatment group had a higher Warburg potential. Altogether, these results suggest that insulin glargine exposure was not involved in tumor initiation but it might have affected tumor progression. Show less
Preclinical and clinical studies reveal that left-sided breast cancer radiotherapy is associated with an increased rate of major coronary events. Consequently, when irradiating women with left... Show morePreclinical and clinical studies reveal that left-sided breast cancer radiotherapy is associated with an increased rate of major coronary events. Consequently, when irradiating women with left-sided breast cancer, specific measures should be taken to decrease the heart dose as much as possible and to avoid radiation-induced coronary artery disease. This thesis focuses on several strategies to optimise the radiation treatment for patients with left-sided breast cancer. With respect to whole breast irradiation we concluded that: __ the routine use of MR images in addition to the CT scan, when delineating either the glandular breast tissue or the lumpectomy cavity, does not have added value. __ tangential IMRT technique combined with a breath-hold technique should be the treatment technique of choice for left-sided breast cancer. __ a breath-hold technique should and can be used in all left-sided breast cancer patients, regardless of age and breast size. __ breath-hold in left-sided whole breast radiotherapy results in a less pronounced increase of coronary calcium score and, hence, could result in less radiation-induced cardio vascular damage. Show less
Intraoperative imaging using near-infrared (NIR) fluorescence is a relatively new technique that can be used to visualize tumor tissue, sentinel nodes and vital anatomical structures. This thesis... Show moreIntraoperative imaging using near-infrared (NIR) fluorescence is a relatively new technique that can be used to visualize tumor tissue, sentinel nodes and vital anatomical structures. This thesis is divided in three parts. In part one the ability to visualize surgical margins using NIR fluorescence imaging is demonstrated. Tumor visualization is established using the clinically approved contrast agent indocyanine green, as well as newly developed tumor targeted probes. The proportion of laparoscopic procedures has steadily increased over the last two decades. A challenging aspect of this conversion to minimal invasive surgery is the lack of tactile information, making it of particular interest for the development and improvement of laparoscopic NIR fluorescence imaging systems. Part two focusses on the clinical implementation of NIR fluorescence guided sentinel lymph node mapping for several indications (e.g. breast, skin and vulvar cancer). Besides visualization of structures that need to be resected (e.g. tumor tissue or sentinel nodes), NIR fluorescence has also the potential to be of value for the identification of structures that should be spared. In part three, we demonstrate the first-in-human application of NIR fluorescence guided ureteral visualization, and also the optimization of bile duct imaging for routine laparoscopic cholecystectomies. Show less
In this thesis the feasibility of tailored follow-up for early-stage breast cancer patients is evaluated. In order to do so, we first determined the risk of locoregional recurrence (LRR) dependent... Show moreIn this thesis the feasibility of tailored follow-up for early-stage breast cancer patients is evaluated. In order to do so, we first determined the risk of locoregional recurrence (LRR) dependent on local treatment in a large cohort of low-risk breast cancer patients, treated with adequate modern systemic therapy. In the second part we evaluated both patients__ and professionals__ needs and preferences for breast cancer follow-up and we reviewed the literature on cost effectiveness of known follow-up schedules. Finally we prospectively examined whether the implementation of a tailored follow-up programme, based on a prognostic index for LRR, is feasible and acceptable to patients and professionals. The results show that in general, implementation of minimised tailored follow-up seems feasible, but professionals tend to more frequent follow-up. Patients accept less intensive follow-up schedules and follow-up by a nurse practitioner. Given the low risk of LRR, tailoring should not only be done based on this risk, but individually, based on the presence of treatment related side effects, either physical or psychosocial. If patients do not experience side effects, annual planned mammography and telephone contact coordinated by a single professional, preferably a specialised nurse, suffice in case of easily accessible information and on demand visits. Show less
Tissue Factor (TF) is a membrane protein that is responsible for the initiation of the coagulation. In addition to its coagulant activity, it can also signal through a member of G-protein coupled... Show moreTissue Factor (TF) is a membrane protein that is responsible for the initiation of the coagulation. In addition to its coagulant activity, it can also signal through a member of G-protein coupled receptor family, PARs, thus play a role in breast cancer growth and angiogenesis. The switch between signaling and coagulant TF regulated by the oxidation/reduction of an allosteric disulfide bond which resides in TF antigen. A decade ago, it was discovered that TF RNA can be alternatively spliced to form a soluble protein called Alternatively Spliced Tissue Factor (asTF). This protein is non-coagulant. However, it plays a major role in breast cancer growth via inducing cancer cell proliferation. The mechanism lying behind behind this phenomenon is asTF's capability to ligate integrins thus it can initiate integrin signaling. Moreover, both TF and asTF can synergize with estrogen pathway thus providing a complex regulation of breast cancer progression. Show less
Currently, 35-45% of newly diagnosed breast cancer patients in developed countries is aged 65 years and older. Older women with breast cancer comprise a heterogeneous group due to large differences... Show moreCurrently, 35-45% of newly diagnosed breast cancer patients in developed countries is aged 65 years and older. Older women with breast cancer comprise a heterogeneous group due to large differences with regard to concomitant diseases, physiological reserve and functional status. Current guidelines for breast cancer are based on studies that were mostly performed in younger patients. Therefore, treatment of older women with breast cancer is not evidence-based, and it cannot be expected that clinical trials will fill this gap of knowledge in the near future. The aim of this thesis was to investigate several aspects of breast cancer treatment in older women. In Part I, several aspects of treatment in older breast cancer patients were assessed. Part II assessed methodological aspects of studying breast cancer in older patients. This thesis has shown that older patients are at increased risk for overdiagnosis of breast cancer due to population screening, with potential harmful effects due to the increased risk of complications of treatment. Despite changing treatment strategies, breast cancer prognosis of older women has not improved. Current treatment strategies and decisions tools are insufficient. Observational studies will become increasingly important in this patient population, the use of accurate methods will be essential. Show less
