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Breast cancer is unanimously considered a highly heterogeneous disease due to its diverse molecular features. Breast tumor kinase (BRK), also known as protein tyrosine kinase 6 (PTK6), is a non-receptor tyrosine kinase that is highly expressed in over 80% of breast carcinomas. The role and mechanism of action of enzymatically activated BRK in breast pathology are unclear. The objectives of this project were to reveal the effect of BRK activation on cell migration, proliferation and tumorigenesis. We also aimed to determine the mechanism of action of BRK in the promotion of cell proliferation. We used BRK-negative cells (MCF10A, MDA-MB-231 and HEK293) to generate three sets of stable cell lines that stably expressed GFP alone, GFP-BRK-WT or GFP-BRK-Y447F (constitutively active) by retroviral infections. We also stably knocked down BRK from BRK-positive cells BT20 and SKBR3 by RNA interference using shRNAs against BRK. Western blotting, immunoprecipitation and qPCR studies were conducted to evaluate protein expression, protein-protein interaction and mRNA expression, respectively. Both sets of cell lines were used to determine the effect of BRK on cell proliferation (automated cell counter), cell migration (transwell and wound healing assay), transformation (colony formation assay) and tumor formation (mouse Xenograft assay). To investigate the mechanism of action of BRK, we validated downstream of tyrosine kinases 1 (Dok1), a tumor suppressor, as a BRK substrate. Deletion or site-directed mutagenesis was performed to map BRK-targeted tyrosines in Dok1 protein. Results obtained from this research project showed that stable expression of the constitutively active mutant of BRK (BRK-Y447F) in MDA-MB-231 cells led to a significant increase in the cell proliferation, migration rate and promoted colony formation and drastically enhanced tumor formation in athymic nude mice in comparison to control cells. Additionally, depletion of BRK abrogated the migration of BT20 and SKBR3 cells. Furthermore, we showed that BRK interacts with and phosphorylates Dok1, inducing Dok1 downregulation via a ubiquitin-proteasome-mediated mechanism. Together, our results show that the activation of BRK is essential for mammary gland tumorigenesis and suggest that targeting of Dok1 for degradation is a novel mechanism of action of BRK in the promotion of cell proliferation, migration and tumor formation.

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Les chiffres mondiaux estiment l’incidence du cancer du sein, cancer féminin le plus fréquent, à 1.3 millions de cas par an, dont près d’un tiers a une issue fatale.La polarité est indispensable à l’organisation cellulaire, ses défauts peuvent mener au cancer. Notre projet est focalisé sur une protéine de la polarité, Lano, et son influence sur le cancer du sein et les CSC. L’Institut Paoli-Calmettes dispose d’environ 10000 échantillons de cancer du sein dont l’analyse montre que la perte de Lano est corrélée à des cancers du sein plus graves et à une augmentation des CSC. Nos résultats in vitro, sur des cellules de cancer du sein humain et in vivo montrent aussi que Lano est un régulateur du nombre de CSC. Les CSC sont une ces causes principales de rechute des patients. La suite de nos travaux pourrait déterminer si Lano est un facteur pronostique de la maladie ou une cible thérapeutique possible. / Breast cancer is the most common cancer in women. Worldwide figures estimate the incidence of breast cancer at 1.3 million cases per year, nearly one third of them has a fatal outcome.Our project focuses on the study of Lano, a polarity protein, in breast cancer and stem cells. The hospital “Institute Paoli-Calmettes” gathered 10,000 breast cancer samples whose analysis shows that the loss of Lano has a role in breast cancer and stem cells. Our in vitro results on human breast cancer cells and in vivo also show that Lano is a regulator of the number of cancer stem cells. Cancer stem cells are one of the major causes of relapse in patients. The rest of our work could determine if Lano could be a prognostic factor of the disease or a possible therapeutic target.

Orientadores: Marcelo Alvarenga, Cesar Cabello dos Santos / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-10T14:34:16Z (GMT). No. of bitstreams: 1 Bianchessi_SusanaTrigo_M.pdf: 5977471 bytes, checksum: 691416790e0a9f01b1b82619e5b6e1f3 (MD5) Previous issue date: 2008 / Resumo: Introdução: A correta avaliação da extensão local do câncer de mama é necessária para a escolha do tratamento local entre cirurgia conservadora e mastectomia. Objetivo: Avaliar se a ressonância magnética (RM) é um bom preditor do tamanho tumoral, multifocalidade e multicentricidade. Sujeitos e Métodos: Vinte mulheres com carcinoma mamário unilateral e unifocal, agendadas para mastectomia, realizaram RM. As medidas dos três diâmetros tumorais foram realizadas em milímetros e outros focos de captação do contraste foram avaliados. O resultado anatomopatológico da peça de mastectomia incluiu os três diâmetros tumorais em milímetros (mm) e descrição de outros focos tumorais, quando presentes. Resultados: Os três diâmetros do tumor foram avaliados e os índices de concordância entre o AP e a RM foram de 95% para o diâmetro longitudinal e 85% para os diâmetros anteroposterior e transversal. A sensibilidade e a especificidade da RM no diagnóstico de doença multifocal foi de 78% e 82%, no diagnóstico de doença multicêntrica foi de 81% e 100% e sua acurácia foi de 80% e 85%. O Índice Kappa em relação a multifocalidade e a multicentricidade foi de 0,6 e 0,63, respectivamente. Conclusão: A RM pode ser usada como método complementar para auxiliar o planejamento cirúrgico / Abstract: Introduction: Predicting the extent of local breast cancer is essential for making the choice between breast-conservation treatment and mastectomy. Aim: To determine whether preoperative breast magnetic resonance (MR) could predict size of index tumor, multifocality and multicentricity. Patients and methods: Twenty women with unilateral end unifocal breast cancer scheduled for mastectomy underwent breast MR. Measurements in the three diameters were taken in millimeters (mm) and other foci of contrast uptake were evaluated. The anatomopathologic (AP) result of the mastectomy specimen included measurements in the three diameters of the index tumor, taken in millimeters, and other foci of tumor. Results: The concordance index was calculated for each diameter and was 95% for longitudinal diameter and 85% for antero-posterior and transversal diameters. The MR sensitivity and specificity for multifocal disease was 78% and 82% and for multicentric disease was 81% and 100%, respectively. The Kappa index was 0,6 for multifocality and 0.63 for multicentricity. Conclusion: MR can be used as a complementary method for surgical planning / Mestrado / Tocoginecologia / Mestre em Tocoginecologia

Orientador: Jacks Jorge Junior / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba / Made available in DSpace on 2018-08-24T16:42:54Z (GMT). No. of bitstreams: 1 SouzaLima_NathaliaCarolinede_M.pdf: 622004 bytes, checksum: 0c706eecc1567182559d2fa1ba1d3900 (MD5) Previous issue date: 2014 / Resumo: Exposição a hormônios sexuais no início da vida pode influenciar a susceptibilidade às doenças relacionadas às diferenças de sexo. A proporção 2D:4D tem sido considerada um marcador putativo de exposição e sensibilidade pré-natal a hormônios sexuais, assim como à expressão de genes relacionados ao câncer. Dessa maneira, essa dissertação propôs-se a investigar a proporção 2D:4D de mulheres com câncer de mama, mulheres com lesão benigna de mama e mulheres controle; e associar 2D:4D com diagnóstico histológico, receptores hormonais, expressão de HER-2 e estadiamento clínico tumoral. No total, 810 mulheres foram recrutadas e classificadas em três grupos: câncer de mama (CM); lesões benignas de mama (LBM); e controle (CON). Mulheres com histórico de injúria nos dedos indicador ou anelar foram excluídas. Todas as mulheres tiveram as palmas das mãos fotografadas utilizando câmera digital acoplada a uma estativa. As imagens foram transferidas para computador e analisadas utilizando o software Adobe Photoshop®, e a distância entre a depressão primária da superfície ventral e a ponta dos dedos indicador (2D) e anelar (4D) das mãos foram medidas duas vezes e registradas. Aos dados foram aplicados os testes de Coeficiente de Correlação Intraclasse, ANOVA, Teste t de Student e teste X². Os resultados mostraram que CM relatou amamentar mais (p=0,0043) e apresentou maior diferença entre as proporções digitais das mão direita e esquerda ( ?D-E ) em comparação ao CON (p=0,0320). Os grupos CM e CON relataram maior paridade em comparação ao grupo LBM (p=0,0157 e p=0,0439, respectivamente). Não houve relação entre 2D:4D e diagnóstico histológico, receptores hormonais, expressão de HER-2 ou estadiamento clínico tumoral. A análise da diferença entre 2D:4D das mãos direita e esquerda (?D-E) sugere que a exposição aos hormônios sexuais intra útero possa influenciar o desenvolvimento de câncer de mama em mulheres adultas / Abstract: Exposure to sex hormones in early life may influence susceptibility to diseases related to sex differences. The ratio 2D:4D has been considered a putative marker of prenatal exposure and sensitivity to sex hormones, as well as the expression of genes related to cancer. Thus, this dissertation aimed to investigate the ratio 2D:4D in breast cancer women, benign breast lesion women and healthy women, and to associate 2D:4D with histological diagnosis, hormone receptor status, HER- 2 expression and tumor clinical staging. Overall, 810 women were recruited and classified into three groups: breast cancer (BC), benign breast lesion (LBM) and control (CON). Subjects with history of injury in the index or ring finger were excluded. All women had their palms of the hands photographed, using a digital camera attached to a stand. The images were transferred to a computer and analyzed using Adobe Photoshop® software, and the distance between primary depression of the ventral surface and the tip of the index finger (2D) and ring finger (4D) were measured twice and recorded. Intraclass correlation coefficient, ANOVA, Student's t test, and X ² test were applied to the data. The results showed that CM reported more breastfeeding habits (p=0.0043) and showed higher ?R-L (p=0.0320) compared to CON. The CM and CON groups reported higher parity compared to LBM group (p=0.0157 and p=0.0439, respectively). Histological diagnosis, hormone receptor status, HER-2 expression, and tumor clinical staging were not associated to 2D:4D. The results of the difference between 2D:4D of the right and left hands (?R-L) suggests that exposure to prenatal sex hormones may influence the development of breast cancer in adult women / Mestrado / Estomatologia / Mestra em Estomatopatologia

Breast cancer has a high propensity to metastasize to bone. While the genetic and epigenetic changes associated with metastatic breast cancer progression are being identified, the changes that drive metastatic progression are poorly understood. Proteases, and in particular matrix metalloproteinases (MMPs), have been shown to play a pivotal role in certain aspects of tumor metastasis by modifying the affected microenvironment. Bone matrix-depositing mouse MC3T3 osteoblasts were co-cultured with metastatic human MDA-MB-23 1 (MDA23 1) cells or the bone-homing MDA-MB 231-1 833/TR (1 833/TR) variant in an effort to identify novel, osteoclast-independent, changes to the tumor/bone microenvironment. Co-culture-induced changes in the complete “protease and inhibitor” expression profile in the osteoblasts and the tumor cells were then determined using targeted murine and human specific microarray chips (CLIP-CHIP TM ). This analysis revealed an increase in the RNA expression of collagenase-3 (MMP 13) in the co-cultured osteoblasts that was confirmed by qPCR. Further, Western blotting indicated increased MIvIP13 protein secretion into the bone matrixltumor microenvironment by the co-cultured MC3T3 cells. The elevation in osteoblast-produced MMP13 was observed when the co- cultured tumor cells were in direct contact or separated by filters. Additionally, the elevation was also induced by conditioned medium derived from separate MDA23 1 or 1 833/TR cultures, which indicates that a soluble factor produced by the tumor cells is capable of inducing MMP 13. One soluble factor that appears to be produced by 1 833iTR cultures is oncostatin M. Oncostatin M is an interleukin-6 family cytokine that is known to upregulate MMP13 synthesis and secretion during chondrogenesis. Genome-wide Affymetrix® analysis revealed, and qPCR analysis confirmed, that oncostatin M receptor-specific subunit RNA was also significantly upregulated in co-cultured osteoblasts. Therefore, breast tumor cells may be capable of initiating protein degradative changes in the bone microenvironment that are independent of the much studied osteolytic degradation initiated by osteoclast activation. / Medicine, Faculty of / Graduate

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Class of 2017 Abstract / Objectives: Specific Aim #1: Describe the incidence and degree of severity of cardiac dysfunction in case studies, retrospective chart analyses, and prospective randomized clinical trials for patients treated with pertuzumab containing regimens for neoadjuvant treatment of locally advanced, inflammatory, or early stage HER2+ BC, or for treatment of metastatic HER2+ BC. Specific Aim #2: Describe the frequency of cardiac safety monitoring for patients undergoing treatment with pertuzumab containing regimens for HER2+ BC within these case studies, retrospective chart analyses, and prospective randomized clinical trials. Methods: Case reports, retrospective chart analyses, and prospective, randomized, controlled trials were identified by search of PubMed and Embase databases, as well as through the Google Scholar search engine. The search strategy included the following keywords: epidermal growth factor receptor 2, erbB-2 genes, pertuzumab, cardiotoxicity, left ventricular function, and left ventricular dysfunction. Reviews were ineligible. All studies that examined the cardiac safety of pertuzumab containing regimens for chemotherapy-naïve HER2+ locally advanced, inflammatory, early stage, or metastatic breast cancer were considered eligible for this systematic review, regardless of sample size. Results: So far, the search strategy retrieved 3 studies that evaluated the cardiac toxicity outcomes of pertuzumab containing regimens. All studies were conducted for chemotherapy-naïve HER2+ locally advanced, inflammatory, early stage, or metastatic breast cancer. Conclusions: The incidence of cardiotoxicity due to treatment with pertuzumab containing regimens for chemotherapy-naïve HER2+ locally advanced, inflammatory, early stage, or metastatic breast cancer remains relatively low. However, the potential severity of cardiac effects related to pertuzumab containing regimens is an important consideration when using these regimens in patients who have any existing risk factors for decreased cardiac function. This systematic review providers a more thorough understanding of the incidence and severity of cardiac adverse effects related to pertuzumab containing regimens since the time pertuzumab was first introduced as an option for HER2+ breast cancer patients.