La résistance aux anti-aromatases (AAs) constitue un obstacle thérapeutique majeur dans le traitement des cancers du sein RE+. Les objectifs de ce travail étaient : (i) de caractériser les événements moléculaires associés à la résistance acquise aux AAs ; (ii) d’identifier de manière globale de nouveaux profils de miRNAs spécifiquement associés à la résistance aux AAs. Notre étude a mis en évidence le rôle central de la voie Akt/mTOR dans la résistance acquise et de novo aux AAs dans des modèles cellulaires, mais également dans des échantillons de patientes ayant récidivé sous anastrozole. La combinaison d’un AA avec le MK-2206, inhibiteur d’Akt ou avec la rapamycine, inhibiteur de mTOR, augmente la sensibilité à l’AA dans les cellules contrôles et est suffisante pour surmonter la résistance et restaurer la sensibilité à l'hormonothérapie dans les cellules résistantes. Notre travail propose également un modèle de résistance acquise aux AAs basé sur la sélection de cellules « cancer-initiating-like » dotées de propriétés d'auto-renouvellement, d’une résistance intrinsèque aux AAs et d’une sensibilité au MK-2206. Notre étude à grande échelle des miRNAs a identifié la voie Akt/mTOR comme une des cibles privilégiées de ces miRNAs. Nous avons identifié et validé trois miRNAs dérégulés capables de moduler le statut d’activation de la voie Akt/mTOR, qui représentent des cibles potentielles. En conclusion, notre projet a mis en évidence de nouvelles voies de signalisations ciblées par ces miRNAs et de nouveaux évènements moléculaires, qui représentent des candidats potentiels dans la résistance aux AAs / Resistance to aromatase inhibitors (AIs) remains a major drawback in the treatment of ER+ breast cancers. Our objectives were (i) to characterize molecular events associated with acquired AI resistance (ii) to capture a global view of the miRNA expression profiles associated with AI resistance. Our results showed the major role of the Akt/mTOR pathway in both de novo and acquired resistance to AI in cellular models and also in breast tumors of patients who relapsed under anastrozole. Combining AI with the Akt inhibitor MK-2206 or with the mTOR inhibitor rapamycin increased sensitivity to this AI in the control cells and was sufficient to overcome resistance and restore sensitivity to endocrine therapy in the resistant cells. Our findings propose a model of AI-acquired resistance based on the selection of cancer-initiating-like cells possessing self-renewing properties, intrinsic resistance to AI and sensitivity to MK-2206. Our large-scale study identified the Akt/mTOR pathway as one of the main targets of the deregulated miRNAs. We identified and validated three miRNAs able to modulate the Akt/mTOR activation status, suggesting these miRNAs as potential targets. To conclude, our project identified new miRNA-targeted signaling pathways and new molecular events, representing strong candidates in the mediation of AI resistance

Yuen Yee Man. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2005. / Includes bibliographical references (leaves 108-125). / Abstracts in English and Chinese. / TITLE PAGE --- p.1 / ACKNOWLEGDEMENTS --- p.2 / ABSTRACT --- p.3 / 摘要 --- p.5 / table of contents --- p.7 / list of figures and tables --- p.13 / CHAPTER 1 GENERAL INTRODUCTION --- p.16 / Chapter 1.1 --- role of PHYTOESTROGENS in soy and red WINE the PREVENTION OF CARDIOVASCULAR DISEASES (CVD) --- p.17 / Chapter 1.1.1 --- INTRoduction and Classification of Phytoestrogens --- p.17 / Chapter 1.1.2 --- estrogenic1ty of phytoestrogens and theIr abundancesin Plasma --- p.18 / Chapter 1.1.3 --- phytoestrogens as one of the active components In cvd Protection --- p.21 / Chapter 1.1.4 --- effects of Phytoestrogens on LDL Receptor and Apolipoprotein A-1 --- p.22 / Chapter 1.2 --- role of estrogen receptors (ers) in gene regulation --- p.24 / Chapter 1.2.1 --- "structure, Classification and tissue distribution of ERS" --- p.24 / Chapter 1.2.2 --- ligands for ERS --- p.25 / Chapter 1.2.3 --- mechaniSMS OF LIgands-ERS complex in GENE regulation --- p.27 / Chapter 1.2.4 --- ligand-independent ER activation --- p.28 / Chapter 1.3 --- aims and scopes of investigation --- p.29 / Chapter CHAPTER 2 --- MATERIALS AND METHODS --- p.30 / Chapter 2.1 --- chemicals and materials --- p.30 / Chapter 2.1.1 --- Chemicals --- p.30 / Chapter 2.1.2 --- Plasmids --- p.30 / Chapter 2.2 --- mammalian cell culture maintainence --- p.30 / Chapter 2.2.1 --- Maintenance of Cells --- p.31 / Chapter 2.2.2 --- Preparation of Cell Stock --- p.31 / Chapter 2.2.3 --- Cell Recovery from Liquid Nitrogen Stock --- p.31 / Chapter 2.3 --- manipulation of dna --- p.31 / Chapter 2.3.1 --- isolation of HEPG2 cells genonmic DNA --- p.31 / Chapter 2.3.2 --- separation and purification of dna from agarose gel --- p.31 / Chapter 2.3.3 --- Restriction digestionof DNA --- p.32 / Chapter 2.3.4 --- Ligation of DNA Fragments --- p.32 / Chapter 2.3.5 --- Transformation of --- p.32 / Chapter 2.3.6 --- Small Scale Plasmids Purification from DH5a --- p.32 / Chapter 2.4 --- construction of expression and reporter plasmids --- p.33 / Chapter 2.4.1 --- Construction of Estrogen Receptorα (Erα) Expression Vectors --- p.33 / Chapter 2.4.2 --- construction of reporter vectors of LDLR promoter and the Respective Mutants --- p.33 / Chapter 2.4.3 --- Construction of Reporter Vectors of APOAI Promoter and the Respective Mutants --- p.33 / Chapter 2.5 --- determination of promoter transcrtiption activities --- p.34 / Chapter 2.5.1 --- Transient Transfection of Cell with ERa Expression Vector and Promoter Reporter using Lipofectamine PLUS Reagent --- p.34 / Chapter 2.5.2 --- Dual Luciferase Assay --- p.34 / Chapter 2.6 --- semi-quantitative and quantitative rt-pcr assay --- p.34 / Chapter 2.6.1 --- Transient transfection of Cell with ERa Expression Vector Using Lipofectamine PLUS Reagent --- p.34 / Chapter 2.6.2 --- "Isolation of RNA using TRIzol® Reagent (Life Technology, USA)" --- p.35 / Chapter 2.6.3 --- Quantitation of RNA --- p.35 / Chapter 2.6.4 --- First Strand cDNA Synthesis --- p.35 / Chapter 2.6.5 --- Sem卜Quantitative PCR Reactions --- p.35 / Chapter 2.6.6 --- Quantitative PCR Reactions --- p.36 / Chapter 2.7 --- western blotting analysis --- p.36 / Chapter 2.8 --- statistical methods --- p.36 / Chapter CHAPTER 3 --- REGULATION BY PHYSIOLOGICAL LEVEL OF 17B-ESTRADIOL ON APOLIPOPROTEIN A-I AND LOW-DENSITY- LIPOPROTEIN RECEPTOR IN HEPG2 CELLS --- p.37 / Chapter 3.1 --- introduction --- p.37 / Chapter 3.2 --- results --- p.39 / Chapter 3.2.1 --- Determination of transient transfection functionality of estrogen receptors in hepg2 cells --- p.39 / Chapter 3.2.2 --- Effect of 17β-Estradiolon LDLR promoter transcription activity --- p.39 / Chapter 3.2.3 --- Effect of 17β-Estradiol on apoai promoter transcription activity --- p.40 / Chapter 3.2 --- discussion --- p.47 / Chapter CHAPTER 4 --- SOY ISOFLAVONES AND RESVERATROL DISPLAY DIFFERENT MECHANISM IN THE UP-REGULATION OF LOVV-DENSITY-LIPOPROTEIN RECEPTOR IN HEPG2 CELLS --- p.49 / Chapter 4.1 --- introduction --- p.49 / Chapter 4.2 --- results --- p.54 / Chapter 4.2.1 --- Association of ERα and isoflavones or resveratrol on LDLR promoter transcription activity --- p.54 / Chapter 4.2.2 --- Association of ERβ and isoflavones or resveratrol on LDLR promoter transcription activity --- p.54 / Chapter 4.2.3 --- "Role of MAP Kinase, PKA and PKC in isoflavones and resveratrol induced LDLR promoter transcription" --- p.55 / Chapter 4.2.4 --- Identification of promoter regions responsible for induction of LDLR transcription by isoflavones in the presence OF ERα --- p.55 / Chapter 4.2.5 --- Identification of promoter regions responsible for induction of LDLR TRANSCRIPTION BY resveratrol IN THE ABSENCE OF ERα --- p.56 / Chapter 4.3 --- DISCUSSION --- p.75 / Chapter CHAPTER 5 --- SOY ISOFLAVONES AND RESVERATROL UP-REGULATE APOLIPOPROTEIN A-I SIMILAR TO 17B-ESTRADIOL IN HEPG2 CELLS --- p.80 / Chapter 5.1 --- INTRODUCTION --- p.80 / Chapter 5.2 --- RESULTS --- p.84 / Chapter 5.2.1 --- Association of ERα phytoestrogens on APCAI gene expression --- p.84 / Chapter 5.2.2 --- Association of ERβ and isoflavones or resveratrol on APOAI promoter transcription activity --- p.85 / Chapter 5.2.3 --- "Role of MAP Kinase, PKA and PKC in isoflavones and resveratrol in APOAI promoter transcription in the presence of ERα" --- p.85 / Chapter 5.2.4 --- Identification of promoter regions responsible for induction of APOAI transcription by isoflavones and resveratrol in the presence of ERα --- p.85 / Chapter 5.3 --- DISCUSSION --- p.100 / Chapter CHAPTER 6 --- GENERAL DISCUSSION --- p.103 / Chapter CHAPTER 7 --- SUMMARY --- p.106 / BIBLIOGRAPHY --- p.108 / APPENDIX 1 ABBREVIATIONS --- p.126 / APPENDIX 2 MATERIALS AND METHODS --- p.129 / APPENDIX 3 PRIMER LISTS --- p.145 / APPENDIX 4 REAGENTS AND BUFFERS --- p.147

No description available.

Malgré de nombreux progrès réalisés dans les traitements des cancers gynécologiques, ceux-ci demeurent la principale cause de mortalité due au cancer chez la femme. Les instabilités chromosomiques et génomiques au niveau du locus 3p21.3 sont des événements fréquents liés à des cancers épithéliaux, notamment les cancers du sein et de l'ovaire. C’est dans cette région que se trouvent les gènes hyaluronidases HYAL-1, HYAL-2 et HYAL-3. HYAL-1 est particulièrement surexprimé dans plusieurs cancers, notamment, le cancer de la prostate, la vessie, le cou, la tête et le sein où il est impliqué dans la progression tumorale et les métastases. Nous avons démontré que dans le locus 3p21.3, HYAL-1 est un gène cible sélectivement réprimé par ERα et l’estrogène. L’analyse de la cohorte METABRIC a révélé une corrélation inverse significative entre l’expression du gène HYAL-1 et ERα. Nous avons identifié des sites de liaison pour ERα au niveau du locus 3p21.3, parmi eux, un ERE proximal était responsable de la répression de HYAL-1 par ERα en plus d’un site Sp-1 requis pour atteindre une répression optimale. Cette répression de HYAL-1 est accompagnée par un enrichissement de la marque répressive H3K27me3 au niveau des deux sites ERE et Sp-1. En plus de réguler l’expression de nombreux gènes, l’activité transcriptionnelle des ERs est aussi régulée par les corégulateurs qui sont recrutés sur les ERs. Nous avons identifié un nouveau partenaire d’interaction inattendu pour les ERs, soit le facteur de transcription hématopoïétique TAL1. Malgré sa réputation d’oncogène dans les leucémies lymphoblastiques aiguës des cellules T, ce facteur de transcription est un corépresseur d’ERα, dû à son effet répresseur direct sur l’activité transcriptionnelle du récepteur en réponse à l’estrogène et donc sur l’expression de ces gènes cible dans le cancer du sein. De plus, TAL1 réprime aussi l’activation d’ERα en réponse à la phosphorylation induite par la voie des MAPK/Erk. Cette répression d’ERα par TAL1 résulte en une diminution de la prolifération et la migration des cellules cancéreuses mammaires. / Despite many advances in treatment of gynecological cancers, they remain the leading cause of cancer death in women. Chromosomal and genome instabilities at the 3p21.3 locus are frequent events related to epithelial cancers, including breast and ovarian cancers. It is in this region that the hyaluronidase HYAL-1, HYAL-2 and HYAL-3 genes are found. HYAL-1 is particularly overexpressed in several cancers, including prostate, bladder, neck, head and breast cancers where it promotes tumor progression and metastasis. We demonstrate here, that in the 3p21.3 locus, HYAL-1 is a target gene selectively repressed by ERα and estrogen. Integrative data mining using METABRIC dataset revealed a significant inverse correlation between ERα and HYAL-1 gene expression in human breast tumors. We identified binding sites for ERα at the 3p21.3 locus, among which a proximal ERE responsible for repression of HYAL-1 by ERα, in addition to an Sp-1 site required to achieve optimal repression. This repression of HYAL-1 is accompanied by an enrichment of the repressive mark H3K27me3 at the two sites ERE and Sp-1. In addition to regulate the expression of many target genes, the transcriptional activity of estrogen receptors is also regulated by coregulators who are recruited on ERs. We identified a new unexpected interaction partner for ERs, the hematopoietic transcription factor TAL1. Despite its reputation as an oncogene in T-cell acute lymphoblastic leukemia, this transcription factor is an ERα-corepressor due to its direct repressive effect on the transcriptional activity of the receptor in response to estrogen and thus to expression of its target genes in breast cancer. Moreover, TAL1 also inhibits ERs activation in response to phosphorylation induced by the MAPK/Erk pathway. This repression of ERα by TAL1 results in decreased growth and migration of mammary cancer cells.

Indiana University-Purdue University Indianapolis (IUPUI) / The time course and biological mechanisms by which breast cancer (BC) and/or alterations in estrogen status lead to cognitive and brain changes remain unclear. The studies presented here use neuroimaging, cognitive testing, genetics, and biomarkers to investigate how post-chemotherapy interval (PCI), chemotherapy-induced amenorrhea (CIA), and genetic variation in the estrogen pathway affect the brain. Chapter 1 examines the association of post-chemotherapy interval (PCI) with gray matter density (GMD) and working memory-related brain activation in BC survivors (mean PCI 6.4, range 3-10 years). PCI was positively associated with GMD and activation in the right frontal lobe, and GMD in this region was correlated with global neuropsychological function. In regions where BC survivors showed decreased GMD compared to controls, this was inversely related to oxidative DNA damage and learning and memory scores. This is the first study to show neural effects of PCI and relate DNA damage to brain alterations in BC survivors. Chapter 2 demonstrates prospectively, in an independent cohort, decreased combined magnitudes of brain activation and deactivation from pre-to post-chemotherapy in patients undergoing CIA compared to both postmenopausal BC patients undergoing chemotherapy and healthy controls. CIA’s change in activity magnitude was strongly correlated with change in processing speed, suggesting this activity increase reflects effective cognitive compensation. These results demonstrate that the pattern of change in brain activity from pre- to post-chemotherapy varies according to pre-treatment menopausal status. Chapter 3 presents the effects of variation in ESR1, the gene that codes for estrogen receptor-α, on brain structure in healthy older adults. ESR1 variation was associated with hippocampus and amygdala volumes, particularly in females. Single nucleotide polymorphism (SNP) rs9340799 influenced cortical GMD and thickness differentially by gender. Apolipoprotein E (APOE)-ε4 carrier status modulated the effect of SNP rs2234693 on amygdala volumes in women. This study showed that genetic variation in estrogen relates to brain morphology in ways that differ by sex, brain region and APOE-ε4 carrier status. The three studies presented here explore the interplay of BC, estrogen, and cognition, showing that PCI, CIA, and ESR1 genotype influence brain phenotypes. Cognitive correlates of neuroimaging findings indicate potential clinical significance of these results.

No description available.

Plus de 70% des tumeurs mammaires expriment le récepteur des œstrogènes alpha (ERα), un facteur de transcription dépendant de ses ligands, les œstrogènes. Deux types d’anti-œstrogènes (AE) peuvent être utilisés en clinique pour traiter ces tumeurs : les SERM (Selective Estrogen Receptor Modulators) qui sont des agonistes partiels, tels que le tamoxifène, le SERM le plus communément utilisé en première ligne de traitement. Les SERD (Selective Estrogen Receptor Degraders) sont des AE purs et induisent la dégradation de ERα. Le fulvestrant a été le premier SERD utilisé en clinique, en seconde ligne de traitement après rechute ou dans un contexte métastatique. Cependant, il est très peu biodisponible oralement. ERα est ubiquitiné en présence de SERD, ce qui conduit à sa dégradation par la voie du protéasome. De plus, nous avons montré qu’ERα est également SUMOylé en présence de fulvestrant et d’autres AE purs. Cette SUMOylation contribue à supprimer ses propriétés transcriptionnelles. La SUMOylation et l’ubiquitination sont deux modifications post-traductionnelles similaires et consistent en la conjugaison d’une petite protéine (SUMO1/2/3 ou ubiquitine) sur des résidus d’une protéine cible lors d’une cascade de réactions impliquant trois enzymes : une enzyme activatrice E1, une enzyme de conjugaison E2 et une ligase E3. Ces processus peuvent être réversibles à l’aide de déSUMOylases (SENP) ou déubiquitinases (DUB). Dans un premier temps, nous avons étudié les déterminants structuraux de ERα nécessaires pour sa SUMOylation. Nos analyses Western et nos tests BRET (Bioluminescence Resonance Energy Transfer), dans lesquels nous avons mesuré le transfert d’énergie entre un donneur luminescent (ERα ou ERβ fusionnés à la luciférase) et un accepteur fluorescent (SUMO1 ou SUMO3 fusionnée à la YFP), ont montré que ERα est SUMOylé en présence de fulvestrant, mais pas son paralogue ERβ. Nous avons ensuite créé des chimères dans lesquelles nous avons échangé les domaines de ERα et de ERβ et avons étudié le profil de SUMOylation de ces chimères à l’aide des mêmes essais. Nous avons ainsi mis en évidence que les séquences spécifiques à ERα dans les hélices H3-H4 du domaine de liaison au ligand sont nécessaires et suffisantes pour sa SUMOylation en présence de fulvestrant. Dans cette région, les acides aminés spécifiques à ERα ne sont pas de potentiels substrats de modification. De plus, ces hélices font partie du sillon de recrutement de cofacteurs de ERα, ce qui suggère qu’il y a un recrutement différentiel de la machinerie de SUMOylation par ERα et ERβ en présence de fulvestrant. Nous avons montré que la surexpression de PIAS1 et PIAS2 peut augmenter le signal de SUMOylation. Nous avons ensuite étudié le lien entre la SUMOylation et l’ubiquitination de ERα induites par les AE. Nous avons adapté nos tests BRET pour mesurer l’ubiquitination de ERα, en réalisant des essais Ubi-BRET (Ubiquitine fusionnée à la YFP). Nous avons ainsi pu observer que la SUMOylation et l’ubiquitination de ERα sont affectées par les mêmes mutations en présence d’AE, suggérant un lien entre ces deux voies de modification de ERα induites par les AEs purs. Des essais en cinétique BRET ont montré que ces modifications se font en parallèle et que l’utilisation d’inhibiteurs de SUMOylation chimiques (ML-792 et TAK-981) ou protéiques (déSUMOylase SENP1/2) abrogent la SUMOylation de ERα. En revanche, l’ubiquitination de ERα par différents AE est partiellement diminuée lorsque ces inhibiteurs sont utilisés. La surexpression des protéines RNF4 et RNF111, qui sont des enzymes E3 ubiquitine ligases qui vont ubiquitiner spécifiquement les protéines SUMOylées (STUbL), augmente l’ubiquitination de ERα en présence de fulvestrant et d’autres SERD, de manière dépendante de la SUMOylation. Cependant, l’inhibition de la SUMOylation par les inhibiteurs ML-792 et TAK-781 n’a pas eu d’effet sur la dégradation de ERα par la voie du protéasome dans les cellules ER-positives MCF-7 et T47D. Ces résultats suggèrent que la SUMOylation et l’ubiquitination de ERα ont lieu en parallèle et nécessitent la même conformation de ERα induite par les AE. Enfin, ces deux modifications peuvent être reliées, grâce aux protéines STUbL de manière spécifique des cellules. En résumé, ces projets nous ont permis de mieux comprendre les mécanismes d’action des anti-œstrogènes purs utilisés dans le cancer du sein ER-positif. Nos découvertes pourront contribuer à anticiper des mécanismes possibles de résistance à ces molécules et permettre d’optimiser le développement de nouveaux anti-œstrogènes plus efficaces dans l’induction de la SUMOylation. / More than 70% of mammary tumors are positives for the expression of the estrogen receptor alpha (ERα), a ligand-dependent transcription factor, activated by estrogens. Two types of antiestrogens (AE) are used in the clinic to treat these tumors: the SERMs (Selective Estrogen Receptor Modulators), which are partial agonists, with the tamoxifen, the most common SERM used in first line of treatment. The SERDs (Selective Estrogen Receptor Degraders) are pure antiestrogens that induced ERα degradation. Fulvestrant has been the first SERD used in the clinic, in second line of treatment after relapse or in a metastatic setting. However, fulvestrant is poorly orally bioavailable. ERα is ubiquitinated in the presence of SERDs and this induce its degradation via the proteasome pathway. In our lab, we have showed that ERα is also SUMOylated in the presence of fulvestrant and other pure antiestrogens. This SUMOylation suppresses its transcriptional properties. SUMOylation and ubiquitination are two similar post-translational modifications that consist in the conjugation of a small protein (SUMO1/2/3 or ubiquitin) on residues of a target protein during an enzymatic cascade implicating three enzymes: an E1 activating, an E2 conjugating and an E3 ligase. These processes are reversible thanks to deSUMOylases (SENPs) and deubiquitinases (DUBs). First, we have studied the structural determinants of ERα required for its SUMOylation. Our Western and BRET (Bioluminescence Resonance Energy Transfer) analyses, where we measured the energy transfer between a luminescent donor (ERα or ERβ fused to the luciferase) to a fluorescent acceptor (SUMO1 or SUMO3 fused to the YFP), have showed that ERα is SUMOylated in the presence of fulvestrant but not its paralog ERβ. We have created chimeras by exchanging domains between ERα and ERβ et we have studied the SUMOylation profile of these chimeras with these assays. We showed that the specific sequence to ERα in the H3-H4 helices of the ligand binding domain are necessary and sufficient to induce its SUMOylation in the presence of fulvestrant. In this region, the amino acids that are specifics to ERα are not potential substrates of modification. Moreover, these helices are part of the cofactor binding groove of ERα, suggesting that there is a differential recruitment of the SUMOylation machinery by ERα compared to ERβ in the presence of fulvestrant. We have also showed that the overexpression of the E3 SUMO ligases PIAS1 and PIAS2 can increase the SUMOylation signal. We then studied the parallel between SUMOylation and ubiquitination of ERα induced by AE. We adapted our BRET assays to measure the ubiquitination of ERα, by performing Ubi-BRET assays (ubiquitin fused to the YFP). We observed that SUMOylation and ubiquitination of ERα are affected by the same mutations in the presence of AE, suggesting that there is a crosstalk between these two modification pathways of ERα induced by AE. BRET kinetic assays showed that these modifications happened in parallel and that the use of SUMOylation inhibitors (chemicals ML-792 and TAK-981; or deSUMOylases SENP1/2) abrogated the SUMOylation of ERα. However, the ubiquitination of ERα by different AE is partially decreased when these inhibitors are used. The overexpression of RNF4 and RNF111, which are SUMO-targeted ubiquitin ligases (STUbLs), that will specifically ubiquitinate SUMOylated target proteins, increased the ubiquitination of ERα in the presence of fulvestrant and other SERDs, in a SUMO-dependent manner. However, the inhibition of SUMOylation by ML-792 and TAK-981 inhibitors did not impact the degradation of ERα induced by the proteasome in ER-positive breast cancer cells MCF7 and T47D. These results suggest that SUMOylation and ubiquitination of ERα happened in parallel and required the same conformation of ERα induced by AE. Finally, these two modifications can be linked thanks to STUbLs in a cell-specific manner. These projects led us to better understand the mechanisms of action of pure AE used in the treatment of ER-positive breast cancer. Our findings will contribute to anticipate possible mechanisms of resistance to AE et will help for the optimization and the development of new AE, more efficient in inducing ERα SUMOylation.

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Normal";mso-tstyle-rowband-size:0;mso-tstyle-colband-size:0;mso-style-noshow:yes;mso-style-priority:99;mso-style-qformat:yes;mso-style-parent:"";mso-padding-alt:0cm 5.4pt 0cm 5.4pt;mso-para-margin-top:0cm;mso-para-margin-right:0cm;mso-para-margin-bottom:10.0pt;mso-para-margin-left:0cm;line-height:115%;mso-pagination:widow-orphan;font-size:11.0pt;font-family:"Calibri","sans-serif";mso-ascii-font-family:Calibri;mso-ascii-theme-font:minor-latin;mso-hansi-font-family:Calibri;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:"Times New Roman";mso-bidi-theme-font:minor-bidi;}</style><![endif]--><b><span style="font-size:11.0pt;font-family:&quot;Times New Roman&quot;,&quot;serif&quot;;mso-fareast-font-family:Calibri;mso-fareast-theme-font:minor-latin;color:black;mso-ansi-language:EN-US;mso-fareast-language:EN-US;mso-bidi-language:AR-SA">Uvod: </span></b><span style="font-size:11.0pt;font-family:&quot;Times New Roman&quot;,&quot;serif&quot;;mso-fareast-font-family:Calibri;mso-fareast-theme-font:minor-latin;color:black;mso-ansi-language:EN-US;mso-fareast-language:EN-US;mso-bidi-language:AR-SA">Karcinom dojke je heterogena bolest koju karakteri&scaron;u različita morfologija, imunohisto-hemijski profil, klinički tok i terapijski odgovor. Ki-67 proliferativni indeks je jedan od markera sa prognostičkim i prediktivnim značajem, čije metodolo&scaron;ko određivanje i analiza jo&scaron; uvek nisu standardizovani. <b>Cilj: </b>Utvrditi graničnu (&ldquo;cut-off&rdquo;) prognostičku vrednost Ki-67 indeksa, kao i povezanost vrednosti Ki-67 u ranom luminalnom karcinomu dojke sa prognostičkim i prediktivnim parametrima karcinoma dojke, kao &scaron;to su životna dob bolesnica, veličina tumora, histolo&scaron;ki gradus (HG) i nivo tumorske ekspresije receptora estrogena (ER) i progesterona (PR). Takođe, cilj istraživanja je i utvrđivanje značajnosti razlike u vrednosti Ki-67 proliferativnog indeksa u odnosu na pojavu lokalnog recidiva, udaljenih metastaza i dužinu preživljavanja u toku petogodi&scaron;njeg perioda praćenja pacijentkinja. <b>Metode: </b>Retrospektivno je analizirano 120 patohistolo&scaron;kih izve&scaron;taja bolesnica kojima je u periodu od 01.01.2009. godine do 31.12.2011. godine na Institutu za onkologiju Vojvodine imunohistohemijskom analizom dokazan luminalni karcinom dojke (pozitivan ER i PR, negativan HER2), bez metastaza u aksilarnim limfnim čvorovima. <b>Rezultati: </b>Metodama deskriptivne statistike prosečna starost pacijentkinja je iznosila 57,42&plusmn;10,17 godina; prosečna veličina tumora 17,98&plusmn;6,97mm; recidiv je registrovan kod 8 (6,7%) pacijentkinja uz prosečan vremenski period do pojave recidiva od 49&plusmn;20,23 meseci. Vrednost &ldquo;cut off&rdquo; indeksa Ki-67 od prognostičkog značaja za vremenski period bez recidiva je iznosio 20,75%. Nije dokazana signifikantna veza između vrednosti Ki-67 i godina starosti pacijentkinja (p=0,401, odnosno p=0,293), kao i jačine ekspresije ER (p=1,00, p=0,957) i PR (p=0,273, p=0,189). Ustanovljena je signifikantna povezanost Ki-67 postoji sa veličinom (p=0,035, p=0,20) i HG tumora (p=0,041, p=0,20). Prosečan period praćenja bolesnica iznosio je 72,92&plusmn;8,38 meseci; nije registrovana pojava udaljenih metastaza, kao ni smrtni ishod. U odnosu na pojavu lokalnog recidiva, Kaplan-Majerovom analizom i Koksovom regresionom analizom proliferativni indeks Ki-67 se pokazao kao signifikantan prediktor za procenu ponovnog javljanja bolesti, lokalnog recidiva (Log rank (df = 1) = 2,73; p=0,045). Takođe je ustanovljeno da je statistički značajan prediktor za procenu recidiva bolesti i starosna dob bolesnica (Log rank (df = 1) = 6,885; p=0,009). Intenzitet pozitivnosti ER i PR, veličina tumora i histolo&scaron;ki gradus se nisu pokazali kao prediktori za pojavu recidiva luminalnih karcinoma dojke (p &gt; 0,05). <b>Zaključak: </b>Zbog heterogene prirode oboljenja, kori&scaron;ćenjem standardnih histopatolo&scaron;kih faktora i biomarkera te&scaron;ko je predvideti tok i ishod karcinoma dojke. Ki-67 je proliferativni marker, čija visoka vrednost korelira sa faktorima lo&scaron;e prognoze.</span></p> / <p><!--[if gte mso 9]><xml> <o:DocumentProperties> <o:Author>Tanja Lakic</o:Author> <o:Version>12.00</o:Version> </o:DocumentProperties></xml><![endif]--><!--[if gte mso 9]><xml> <w:WordDocument> <w:View>Normal</w:View> <w:Zoom>0</w:Zoom> <w:TrackMoves/> <w:TrackFormatting/> <w:PunctuationKerning/> <w:ValidateAgainstSchemas/> <w:SaveIfXMLInvalid>false</w:SaveIfXMLInvalid> <w:IgnoreMixedContent>false</w:IgnoreMixedContent> <w:AlwaysShowPlaceholderText>false</w:AlwaysShowPlaceholderText> <w:DoNotPromoteQF/> <w:LidThemeOther>EN-US</w:LidThemeOther> <w:LidThemeAsian>X-NONE</w:LidThemeAsian> <w:LidThemeComplexScript>X-NONE</w:LidThemeComplexScript> <w:Compatibility> <w:BreakWrappedTables/> <w:SnapToGridInCell/> <w:WrapTextWithPunct/> <w:UseAsianBreakRules/> <w:DontGrowAutofit/> <w:SplitPgBreakAndParaMark/> <w:DontVertAlignCellWithSp/> <w:DontBreakConstrainedForcedTables/> 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Normal";mso-tstyle-rowband-size:0;mso-tstyle-colband-size:0;mso-style-noshow:yes;mso-style-priority:99;mso-style-qformat:yes;mso-style-parent:"";mso-padding-alt:0cm 5.4pt 0cm 5.4pt;mso-para-margin-top:0cm;mso-para-margin-right:0cm;mso-para-margin-bottom:10.0pt;mso-para-margin-left:0cm;line-height:115%;mso-pagination:widow-orphan;font-size:11.0pt;font-family:"Calibri","sans-serif";mso-ascii-font-family:Calibri;mso-ascii-theme-font:minor-latin;mso-hansi-font-family:Calibri;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:"Times New Roman";mso-bidi-theme-font:minor-bidi;}</style><![endif]--></p><p class="Default"><b><span style="font-size:11.0pt">Introduction: </span></b><span style="font-size:11.0pt">Breast cancer is a heterogeneous disease characterized by different morphology, immunohistochemical profile, clinical course and response to applied therapy. Ki-67 proliferative index is one of the prognostic and predictive factors, whose methodological determination and analysis are still unstandardized. <b>Objective: </b>Determination of cut-off value for Ki-67 index, its corelation in luminal breast carcinoma with patient&#39;s age, tumor size, histological grade (HG) and expression of estrogen (ER) and progesterone (PR). Also, the aim of the study was to determine the significance of the difference in the value of the Ki-67 proliferative index in relation to the occurrence of local relapse, distant metastases and survival rates during the five-year follow-up period of the patient. <b>Methods: </b>Retrospectively, we analysed 120 pathohistological reports of patients who were treated in the period from 01.01.2009 until 31.12.2011 at the Oncology Institute of Vojvodina, and to whom immunohistochemically was proven luminal breast cancer (positive ER and PR, negative HER2), without axillary lymph node metastases. </span><b><span style="font-size:11.0pt">Results: </span></b><span style="font-size:11.0pt">The average patient&rsquo;s age was 57.42&plusmn;10.17 years; average tumor size 17.98&plusmn;6.97mm; recurrence was registered in 8 (6.7%) patients with average recurrence time of 49&plusmn;20.23 months. &quot;Cut off&quot; Ki-67 value of prognostic significance for period without recurrence was 20.75%. Test didn&rsquo;t show significant relationship between Ki-67 and patient&rsquo;s age (p=0.401 and p=0.293), as well as the strength of expression ER (p=1.00, p=0.957) and PR (p=0.273, p=0.189). Significant correlation was present for Ki-67 with size (p=0.035, p=0.20) and tumor&rsquo;s HG (p=0.041, p=0.20). The average follow-up period for patients was 72.92&plusmn;8.38 months; there was no registered occurrence of distant metastases or fatal outcome. In relation to the occurrence of local relapse, Kaplan-Meier analysis and Cox regression analysis, the proliferative index Ki-67 proved to be a significant predictor for the assessment of recurrence of the disease, local relapse (Log rank (df = 1) = 2.73; p = 0.045). Also, it was founded that a statistically significant predictor for assessing the recurrence of the disease is the age of the patients (Log rank (df = 1) = 6.885; p = 0.009). The intensity of ER and PR expression, tumor size and histological grade have not been shown to be predictors of the recurrence of luminal breast carcinoma (p&gt; 0.05). </span><b><span style="font-size:11.0pt">Conclusion: </span></b><span style="font-size:11.0pt">Breast carcinoma is heterogeneous disease, so it is difficult to predict its course and outcome using standard histopathological factors and biomarkers. Ki-67 is proliferative marker whose high value correlates with factors of bad prognosis. </span></p>