Breast cancer is the most common malignancy diagnosed in women1. The incidence of breast cancer increases with age; currently, in developed countries more than 40% of breast cancer patients is 65... Show moreBreast cancer is the most common malignancy diagnosed in women1. The incidence of breast cancer increases with age; currently, in developed countries more than 40% of breast cancer patients is 65 years or older at diagnosis1. In the Netherlands in 2011, 5,441 women aged 65 years or older were diagnosed with breast cancer2. The remaining life expectancy of persons aged 65 is still increasing, from almost 19 years in 1980, up to more than 21 years in 2010. Moreover, in last decades the birth rate has decreased, resulting in a higher proportion of older persons in the general population3. Both an increasing life expectancy and the increasing number of elderly in the population will further enhance the number of elderly women confronted with breast cancer Show less
The aim of the work included in this PhD thesis was to explore the diverse application possibility of using NIR fluorescent probes with specific properties to visualize and characterize cancer and... Show moreThe aim of the work included in this PhD thesis was to explore the diverse application possibility of using NIR fluorescent probes with specific properties to visualize and characterize cancer and cell death. In this thesis, we mainly focus on optical imaging and its application, both at microscopic and macroscopic level. Because we believe optical imaging in particular represents a technology that has unique potential to exploit further our knowledge in preclinical research. First, we imaged breast tumors and their metastases using combinations of four NIR fluorescent probes that possess different optical imaging properties. Then, we studied two different NIR fluorescent probes, PSVue and a heat shock protein-90 alkylator (NIR fluorescent conjugate of GSAO), which can be used to non-invasively imaging cell death with different optical modules in a mouse model of traumatic brain injury. Next, we employed the NIR fluorescently tagged GSAO as a biomarker for monitoring breast cancer cell death after chemotherapy. Moreover, we provides a general discussion about the advantages and the challenging that the state-of-art optical imaging is facing and shares some future prospective. This thesis ends with a summary that outlined the major findings of studies described in different chapters and explored the clinical implications. Show less
Not all hormone receptor positive breast cancer patients benefit from tamoxifen treatment, but may be nonetheless exposed to its side effects (e.g. hot flashes). Tamoxifen needs bioactivation by... Show moreNot all hormone receptor positive breast cancer patients benefit from tamoxifen treatment, but may be nonetheless exposed to its side effects (e.g. hot flashes). Tamoxifen needs bioactivation by formation of the metabolite endoxifen, which is mainly catalyzed by the enzyme CYP2D6. In this thesis, we studied the variation in tamoxifen metabolism in relation to endoxifen serum concentration, tamoxifen efficacy and side effects, focusing on CYP2D6 activity and pharmacogenetics. The importance of good methodology for genotyping and endoxifen measurement was exemplified. In a large trial population, no association between CYP2D6 genotype and disease free survival or the occurence of hot flashes was found, although polymorphisms in the estrogen receptor-1 and UGT2B15 might be related to clinical outcome. Adherence, but not the concomitant use of CYP2D6 inhibiting medication was associated with breast cancer recurrence. CYP2D6 genotype and endoxifen-guided tamoxifen dose escalation led to an increase in endoxifen serum levels and a new 13C-Dextromethorphan breath test was used for phenotyping CYP2D6, which correlated well with CYP2D6 genotype and endoxifen levels. Finally, the CYP2D6 phenotype and endoxifen serum levels are currently prospectively related to breast cancer recurrence. This may lead to therapeutic drug monitoring and selection of patients who benefit most from tamoxifen. Show less
The primary aim of this thesis is to gain insight into which search facilities for spontaneously published stories facilitate breast cancer patients in finding stories by other patients in a... Show moreThe primary aim of this thesis is to gain insight into which search facilities for spontaneously published stories facilitate breast cancer patients in finding stories by other patients in a similar situation. According to the narrative approach, social comparison theory, and social cognitive theory, reading stories about similar others may have the most positive impact. The research followed a user-centred design: users of search facilities (i.e., patients who want to read stories written by others) were involved in every phase of the research so that the search facilities could be tailored to these users__ needs and preferences instead of forcing users to change their search behaviour to conform to search facilities that were developed without their involvement. We examined which breast cancer patients spontaneously publish their story online and which themes they write about in their stories, and how these stories are presented and disclosed on websites. We then examined which topics and writer characteristics patients prefer to search for and translated these preferences into search facilities. Finally, we examined which search facilities show the most positive effects on patient satisfaction and search success, and how patients actually search for stories written by others. The research was conducted from a clinical informatics perspective, using knowledge from the fields of information retrieval, human-computer interaction and psychology. Show less
Despite extensive studies to unravel molecular mechanisms underlying breast cancer metastasis, still 3500 women die of the results of this disease in the Netherlands each year. Improving our... Show moreDespite extensive studies to unravel molecular mechanisms underlying breast cancer metastasis, still 3500 women die of the results of this disease in the Netherlands each year. Improving our understanding of metastasis formation remains a challenge for further drug development. The scope of this thesis is the identification of novel candidate metastasis genes, with a main focus on candidate genes affecting tumor cell migration. For that purpose, a live cell imaging-based random cell migration assay that is suitable for screening has been developed. In addition, a mouse breast cancer model that allows to study tumor cell autonomous processes of metastasis formation is described. A RNA-interference tumor cell migration screen has been done and resulted in the identification of novel regulators of tumor cell migration that show clinical relevance in a breast cancer patient cohort. In addition, focused research has been conducted on two previously identified candidate metastasis genes to determine their role in breast cancer metastasis. Show less
TGF-beta and BMPs are members of the TGF-beta superfamily of cytokines which play an important role in a multitude of processes. In cancer, TGF-beta is known for its dual role: in early stages it... Show moreTGF-beta and BMPs are members of the TGF-beta superfamily of cytokines which play an important role in a multitude of processes. In cancer, TGF-beta is known for its dual role: in early stages it inhibits cancer cell proliferation, whereas in later stages it promotes invasion and metastasis. In this thesis, a 3 dimenstional model to monitor TGF-beta-induced invasion of breast cancer cells is presented and an important role for MMP2 and MMP9. Furthermore, BMP-7 could inhibit TGF-beta-induced invasion through inhibition of TGF-beta-induced integrin beta3 expression. The property of TGF-beta to induce epithelial to mesenchymal transition (EMT) is thought to contribute to its pro-invasive effect. We found that transcription factors involved in this process induce invasion. Lastly, we identified kinases involved in BMP signaling. These findings help the understanding of breast cancer cell invasion and a way to prevent this process. Show less
The aim of this work was to develop methods to measure structural changes in the skeleton using MicroCT. In addition, these new methods should be able to quantify biologically relevant changes. In... Show moreThe aim of this work was to develop methods to measure structural changes in the skeleton using MicroCT. In addition, these new methods should be able to quantify biologically relevant changes. In order to do this, normalized methods to analyse MicroCT scans and perform quantitative measurements within these datasets are described in this thesis. These techniques were combined with a biological angiogenesis assay and used as research tools in a study comparing various different combination treatments of bone metastases. Show less
Damiano, L.; Le Devedec, S.E.; Di Stefano, P.; Repetto, D.; Lalai, R.A.; Truong, H.; ... ; Defilippi, P. 2012
This thesis consists of two parts. In part I, we have demonstrated that preoperatively administrated systemic (neoadjuvant) therapy is a feasible treatment strategy in early stage breast cancer to... Show moreThis thesis consists of two parts. In part I, we have demonstrated that preoperatively administrated systemic (neoadjuvant) therapy is a feasible treatment strategy in early stage breast cancer to achieve improved surgical options and to assess tumor response. We also demonstrated that overexpression of the breast cancer stem cell marker aldehyde dehydrogenase-1 in early stage breast cancer patients is inversely associated with age and is of prognostic importance. In part II, we have demonstrated proof-of-principle of intraoperative tumor detection and image-guided tumor resection by using the novel technique of near-infrared fluorescence imaging. We have performed two clinical trials to optimize the use of indocyanine green as a near-infrared fluorescence lymphatic tracer for the sentinel lymph node procedure in breast cancer patients. Show less
Women from families in which many individuals have developed breast and/or ovarian cancer may request for DNA-testing. A DNA-test result may disclose their own risks to develop cancer (again),... Show moreWomen from families in which many individuals have developed breast and/or ovarian cancer may request for DNA-testing. A DNA-test result may disclose their own risks to develop cancer (again), their relatives__ risks and subsequent options for medical surveillance. This thesis describes several multicenter studies in the Netherlands about the psychological and medical impact of DNA-testing on the lives of these women and their relatives. Despite their accurate understanding of the global meaning of DNA-test result, many participants interpreted the result differently from what the genetic-counselor had actually communicated. Like in a children__s whisper game, their relatives also misinterpreted the information communicated by the first messenger. The messengers__ misinterpretation was not only related to their inaccurate thoughts about heredity and cancer in general, but also to their feelings, and especially to their unfulfilled need for certainty, sense of self and unresolved existential issues. The presence of misinterpretations predicted the extent of the counselees' distress and the medical decisions after DNA-test result disclosure. The study results are described in their historical and theoretical context, followed by practical clinical suggestions for genetic-counselors and psychologists. For instance, we suggest that genetic-counselor try to avoid the communication of ambiguous DNA-test results that do not have medical consequences. Show less
Despite major advances in breast cancer diagnostics and treatment over the years, the disease is still a leading cause of death in women worldwide. Primary breast tumors can be treated relatively... Show moreDespite major advances in breast cancer diagnostics and treatment over the years, the disease is still a leading cause of death in women worldwide. Primary breast tumors can be treated relatively well with radiation, surgery, chemotherapy or a combination of these treatments. The occurrence of distant metastases derived from the primary tumor however, results in a considerable decrease in disease prognosis. Metastasis formation occurs through a series of distinct cell biological steps (outlined above). Understanding the molecular mechanisms that underlie each of these steps will help in the development of more successful anti-metastasis treatments. In this thesis, both in vitro and in vivo studies are described that aim at unraveling some of the processes involved in metastasis formation: signaling by components of the focal adhesions and cell migration. Show less
In het proefschrift van Martine van Miltenburg wordt het onderzoek naar de rol van FAK en annexine A1 in borstkankerontwikkeling en uitzaaiing (metastasering) beschreven. E__n van de... Show moreIn het proefschrift van Martine van Miltenburg wordt het onderzoek naar de rol van FAK en annexine A1 in borstkankerontwikkeling en uitzaaiing (metastasering) beschreven. E__n van de sleutelprocessen bij de metastasering is de verandering van het rustige fenotype van kankercellen naar het beweeglijke fenotype. Een belangrijke ontdekking is dat het eiwit annexine A1 een belangrijke rol speelt in metastasering van basale borstkanker. Verhoogde expressie van annexine A1 draagt bij aan beweeglijkheid en daarmee agressief gedrag van tumorcellen. Hoe hoger de expressie van annexine A1, hoe meer uitzaaiingen, simpel gezegd. Wanneer annexine A1 wordt uitgeschakeld in deze cellen verandert de cel van het agressieve gedrag naar een ___rustige___ tumorcel, en ontstaan er beduidend minder uitzaaiingen. Ondanks de veelbelovende resultaten is het geen optie om remming van annexine A1 als anti-kanker therapie te gebruiken omdat annexine A1 ook in gezonde lichaamscellen een belangrijke functie heeft. Maar de onderzoekers denken wel dat annexine A1 een ___marker___ voor basale borstkanker kan worden. Doordat annexine A1 specifiek in basale borstkanker verhoogd tot expressie komt zou het als marker wellicht goed gebruikt kunnen worden om dit relatief agressieve type borstkanker type te bepalen bij pati__nten. Show less
The skeleton is one of the most common organs to be affected by metastatic disease. However, only a restricted number of solid cancers, especially those of the breast and prostate, are responsible... Show moreThe skeleton is one of the most common organs to be affected by metastatic disease. However, only a restricted number of solid cancers, especially those of the breast and prostate, are responsible for the majority of the bone metastases. Bone metastases are a major cause of morbidity, characterized by severe pain and high incidence of fractures, spinal cord compression and bone marrow aplasia requiring hospitalization. Despite the high frequency of skeletal metastases, the molecular mechanisms underlying the predisposition for tumors to colonize bone are poorly understood and treatment options are often unsatisfactory. The focus of this thesis was to better understand the processes that contribute to the formation of distant metastasis (chapter 2), particularly to bone (chapter 4__7), as well as to explore new treatment strategies with conventional (chapter 4 and 5) and novel therapeutic molecules (chapter 6 and 7) using optical imaging to sensitively monitor growth, dissemination and metastasis in mouse models (chapter 3__7). Show less
Le, Dévédec S.E.; Roosmalen, W.P.E. van; Maria, N.; Grimbergen, M.; Pont, C.M.; Lalai, R.A.; Water, B. van de 2009
This thesis describes the search for new high-risk breast cancer susceptibility genes by linkage analysis. To date 20-25% of familial breast cancer is explained by mutations in the high-risk BRCA1... Show moreThis thesis describes the search for new high-risk breast cancer susceptibility genes by linkage analysis. To date 20-25% of familial breast cancer is explained by mutations in the high-risk BRCA1 and BRCA2 breast cancer susceptibility genes. For the remaining families the genetic etiology is unknown. It is still possible that other high-penetrant genes play a role. Although a polygenic model with multiple low-penetrant genes acting additive or multiplicative will probable explain most of the BRCA1/2 negative families. Linkage in an international set of 150 high-risk breast cancer families couldn__t identify high-risk genes. However when limiting the linkage analysis to Dutch families only, we identified 9q21-22 as a putative breast cancer susceptibility locus Show less
Given the natural history of colorectal and breast cancer, early diagnosis appears to be the most appropriate tool to reduce disease-related mortality.[6;7] Currently, there is no early diagnostic... Show moreGiven the natural history of colorectal and breast cancer, early diagnosis appears to be the most appropriate tool to reduce disease-related mortality.[6;7] Currently, there is no early diagnostic test with high sensitivity, specificity and positive predictive value, which can be used as a routine screening tool. Therefore, there is a need for new biomarkers for both types of cancer that can improve early diagnosis, monitoring of disease progression and therapeutic response and detect disease recurrence. Proteomic expression profiles generated with mass spectrometry have been suggested as potential tools for the early diagnosis of cancer and other diseases. Because it is still in its infancy, many problems have to be overcome before clinical proteomics can be transferred form bench to bedside. Chapter 2 gives an insight in the different fields of translational research in colorectal cancer by our group. In chapter 3 reliability of human serum protein profiling using MALDI-TOF mass spectrometry is analysed. We present a pipeline for pre-processing, statistical data analysis and presentation of MALDI-TOF spectra. This novel analysis method was used to assess the effect of variable pre-analytical conditions on human serum protein profiles, and their effect on reproducibility. In line with the logistic conditions in a routine clinical setting, the effects of sample handling and storage, and also circadian rhythm factors on the serum protein profiles were analysed. In chapter 4 and 5 the feasibility of mass spectrometry based protein profiling for the discrimination of colorectal cancer patients from healthy individuals was assessed. In addition to standardizing technical factors and biological variations, we performed blinded tests and employed a randomised block design experimentation to minimize impact of potential confounding factors and to avoid bias. Especially, validation of our classifier, as a possible pitfall, was given much attention. Therefore, we performed a linear discriminant analysis with double cross-validation to separate cancer patients from healthy subjects. Chapter 6 reports on results from an identical designed protein profiling study for the detection of breast cancer. In chapter 7 a first validated study on the detection of breast cancer based on mass spectrometry generated protein profiles is described. In this study the same randomised blocked design and double cross validation is used, however the classifier was validated in an independent set of new patients and controls. Finally, the results and conclusions of all above mentioned studies and especially the current status of clinical proteomics in cancer are discussed in chapter 8. A Dutch summary of this thesis is written in chapter 9. Show less
In order to form a distant metastasis, a cancer cell has to migrate out of the primary tumor, intravasate into a blood or a lymphatic vessel, subsequently survive in the absence of cell-cell and... Show moreIn order to form a distant metastasis, a cancer cell has to migrate out of the primary tumor, intravasate into a blood or a lymphatic vessel, subsequently survive in the absence of cell-cell and cell-matrix interactions, extravasate the blood or lymphatic vessel, migrate through the target organ and finally proliferate to grow out into a full metastasis. During all of these processes, specific kinases are involved in the concerted activation of distinct signaling pathways. We hypothesised that the protein tyrosine kinase FAK plays a crucial role in one or multiple of the processes involved in the formation of metastases. Therefore, the overall aim of the studies described in this thesis was to investigate the role of the non-receptor protein tyrosine kinase FAK in the distinct processes involved in tumorigenesis and metastasis and to unravel the involved downstream signaling pathways. Moreover, the potential of a combined therapy of the inhibition of FAK and exposure to the cytostatic doxorubicin was tested, as well as dissection of the intracellular events downstream of FAK. Show less
The cumulative lifetime risk of developing breast cancer for a Dutch woman is about 12%. In some families breast cancer seems to occur even more frequently or women fall ill at a relatively young... Show moreThe cumulative lifetime risk of developing breast cancer for a Dutch woman is about 12%. In some families breast cancer seems to occur even more frequently or women fall ill at a relatively young age. Such families may have a genetic susceptibility towards breast cancer. To learn more about the likelihood of this susceptibility actually being present, members of such families may request genetic counselling and DNA-testing. The main purpose of this thesis is to provide more insight into some effects of genetic counselling and DNA testing for breast cancer. We address effects on: (a) risk perception; (b) psychological distress; and (c) intentions for risk-management behaviour. Regarding the effects of DNA testing, special attention is paid to women who receive a so-called uninformative DNA-test result. The data of this thesis do not provide support for one of the two hypotheses which has been postulated about the impact of an uninformative result. They suggest that, as a group, women seem to be reassured upon learning their uninformative result, but to a lesser extent than women who received a true negative result. Only a small minority of women with an uninformative result incorrectly concluded that the chance of a mutation being present was non-existent. Show less
Dit proefschrift behelst een aantal klinische studies met betrekking tot de behandeling van borstkanker. Zowel aspecten van de locoregionale behandeling, d.w.z. chirurgie en bestraling, als van de... Show moreDit proefschrift behelst een aantal klinische studies met betrekking tot de behandeling van borstkanker. Zowel aspecten van de locoregionale behandeling, d.w.z. chirurgie en bestraling, als van de systemische behandeling, d.w.z. chemotherapie en hormonale therapie, worden belicht. Het proefschrift bestaat uit drie delen. Het eerste deel behelst de rol van de timing van chemotherapie t.o.v. de operatie bij de behandeling van borstkanker. Hieruit blijkt onder meer dat het geven van chemotherapie voorafgaand aan de operatie leidt tot "krimpen" van het gezwel en derhalve tot een stijging in het aantal borstsparende behandelingen. In deel twee wordt de rol van de locoregionale behandeling, d.w.z. chirurgie en bestraling, bij borstkanker bestudeerd. Tevens worden potenti_le voorspellende factoren voor het optreden van een lokaal recidief bestudeerd. Met name jonge vrouwen die borstsparende therapie ondergaan blijken een verhoogd risico te hebben op het optreden van een lokaal recidief. Het optreden van het lokale recidief lijkt voorspeld te kunnen worden door overexpressie van de tumorcel marker, genaamd PS6K. In deel drie wordt dieper ingegaan op vrouwen jonger dan veertig jaar met borstkanker. Deze groep vrouwen heeft een slechte prognose vergeleken met oudere vrouwen en de oorzaak hiervoor is onduidelijk. Derhalve wordt op dit moment geadviseerd om iedere vrouw jonger dan 35 jaar met borstkanker te behandelen met chemotherapie. In deel 3 wordt aangetoond dat er wel degelijk jonge vrouwen te identificeren zijn met een goede prognose waarbij de vraag gesteld kan worden of het geven van chemotherapie bij deze vrouwen wel noodzakelijk is. Show less
Cortactine wordt gecodeerd door het gen EMS1 dat op het chromosoom 11q13 ligt. Het 11q13 gebied is geamplificeerd in een deel van de borsttumoren dat geassocieerd is met cortactine overexpressie en... Show moreCortactine wordt gecodeerd door het gen EMS1 dat op het chromosoom 11q13 ligt. Het 11q13 gebied is geamplificeerd in een deel van de borsttumoren dat geassocieerd is met cortactine overexpressie en de aanwezigheid van lymfeklier metastasen en een verhoogde sterfte. Cortactine is een F-actine bindend eiwit dat betrokken is bij de regulatie van het actine cytoskelet, dat belangrijk is bij cel migratie. Agnes van Rossum onderzocht de rol van cortactine (over)expressie op cel biologische processen die betrokken zijn bij de ontwikkeling en/of het gedrag van borstkanker. Zij ontdekte onder meer dat er cortactine varianten zijn die de cel migratie beïnvloeden. Verder lijkt cortactine een rol te spelen bij intercellulaire cel adhesie en cel spreiding. Een studie met cortactine transgene muizen toonde aan dat cortactine geen oorzakelijke rol heeft in het ontstaan van borstkanker. Van Rossum vermoedt dat cortactine de binding tussen cellen en hun omgeving dusdanig kan beïnvloeden dat deze gemakkelijker uit de oorspronkelijke tumor kunnen ontsnappen en gaan migreren. Show less
