2,820 research outputs found

    Correlation between hepatocyte growth factor receptor and vascular endothelial growth factor-A in breast carcinoma.

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    The aim of the study was to evaluate the prognostic value of the vascular endothelial growth factor A (VEGF-A) and hepatocyte growth factor receptor (HGFR, c-met) expressions in homogenous group of breast cancer patients. Tumor samples were collected from 98 patients with invasive ductal breast carcinoma stage II treated with primary surgery. We have observed a strong correlation between VEGF-A and c-met. No correlations were found between VEGF-A or HGFR expressions and clinical parameters (tumor size, grade, axillary lymph node status, age), 5- and 10-years DFS or OS. Our study did not reveal any prognostic value of c-met or VEGF. In addition they are not useful to separate a patients' subgroup with poor prognosis. Unlike in other authors' studies, our patients' group is very homogenous which might tribute to obtained results

    Eukaryotic Initiation Factor 4E (eIF4E) and angiogenesis: prognostic markers for breast cancer

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    BACKGROUND: The overexpression of eukaryotic translation initiation factor 4E (eIF4E), a key regulator of protein synthesis, is involved in the malignant progression of human breast cancer. This study investigates the relationship between eIF4E and angiogenesis, as well as their prognostic impact in patients with human breast cancer. METHODS: Immunohistochemical staining was used to determine protein expression of eIF4E, vascular endothelial growth factor (VEGF), interleukin-8 (IL-8), and CD105 in a set of 122 formalin-fixed, paraffin-embedded primary breast cancer tissues. Expression of eIF4E in positive cells was characterized by cytoplasmic staining. Evaluation of VEGF and IL-8 in the same tissue established the angiogenic profiles, while CD105 was used as an indicator of microvessel density (MVD). RESULTS: A significant relationship was found between the level of eIF4E expression and histological grade (P = 0.016). VEGF, IL-8, and MVD were closely related to tumor grade (P = 0.003, P = 0.022, and P < 0.001, respectively) and clinical stage (P = 0.007, P = 0.048, and P < 0.001, respectively). Expression of eIF4E was also significantly correlated with VEGF (P = 0.007), IL-8 (P = 0.007), and MVD (P = 0.006). Patients overexpressing eIF4E had significantly worse overall (P = 0.01) and disease-free survival (P = 0.006). When eIF4E, histological grade, tumor stage, ER, PR, Her-2 status and the levels of VEGF, IL-8, MVD were included in a multivariate Cox regression analysis, eIF4E emerged as an independent prognostic factor for breast cancer (P = 0.001), along with stage (P = 0.005), node status (P = 0.046), and MVD (P = 0.004). CONCLUSION: These results suggest that higher eIF4E expression correlates with both angiogenesis and vascular invasion of cancer cells, and could therefore serve as a useful histological predictor for less favorable outcome in breast cancer patients, as well as represent a potential therapeutic target

    Hypoxia-inducible factor-2a is associated with ABCG2 expression, histology-grade and Ki67 expression in breast invasive ductal carcinoma

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    <p>Abstract</p> <p>Background</p> <p>Breast cancer is the most common cancer and the leading cause of cancer mortality in women worldwide. Hypoxia is an important factor involved in the progression of solid tumors and has been associated with various indicators of tumor metabolism, angiogenesis and metastasis. But little is known about the contribution of Hypoxia-Inducible Factor-2a (HIF-2a) to the drug resistance and the clinicopathological characteristics in breast cancer.</p> <p>Methods</p> <p>Immunohistochemistry was employed on the tissue microarray paraffin sections of surgically removed samples from 196 invasive breast cancer patients with clinicopathological data. The correlations between the expression of HIF-2a and ABCG2 as well as other patients' clinicopathological data were investigated.</p> <p>Results</p> <p>The results showed that HIF-2a was expressed in different intensities and distributions in the tumor cells of the breast invasive ductal carcinoma. A positive staining for HIF-2a was defined as a brown staining observed mainly in the nucleus. A statistically significant correlation was demonstrated between HIF-2a expression and ABCG2 expression (p = 0.001), histology-grade (p = 0.029), and Ki67 (p = 0. 043) respectively.</p> <p>Conclusion</p> <p>HIF-2a was correlated with ABCG2 expression, histology-grade and Ki67 expression in breast invasive ductal carcinoma. HIF-2a could regulate ABCG2 in breast cancer cells, and could be a novel potential bio-marker to predict chemotherapy effectiveness. The hypoxia/HIF-2a/ABCG2 pathway could be a new mechanism of breast cancer multidrug-resistance.</p> <p>Virtual slides</p> <p>http://www.diagnosticpathology.diagnomx.eu/vs/2965948166714795</p

    An expression signature of syndecan-1 (CD138), E-cadherin and c-met is associated with factors of angiogenesis and lymphangiogenesis in ductal breast carcinoma in situ

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    INTRODUCTION: Heparan sulphate proteoglycan syndecan-1 modulates cell proliferation, adhesion, migration and angiogenesis. It is a coreceptor for the hepatocyte growth factor receptor c-met, and its coexpression with E-cadherin is synchronously regulated during epithelial-mesenchymal transition. In breast cancer, changes in the expression of syndecan-1, E-cadherin and c-met correlate with poor prognosis. In this study we evaluated whether coexpression of these functionally linked prognostic markers constitutes an expression signature in ductal carcinoma in situ (DCIS) of the breast that may promote cell proliferation and (lymph)angiogenesis. METHODS: Expression of syndecan-1, E-cadherin and c-met was detected immunohistochemically using a tissue microarray in tumour specimens from 200 DCIS patients. Results were correlated with the expression patterns of angiogenic and lymphangiogenic markers. Coexpression of the three prognostic markers was evaluated in human breast cancer cells by confocal immunofluorescence microscopy and RT-PCR. RESULTS: Coexpression and membrane colocalization of the three markers was confirmed in MCF-7 cells. E-cadherin expression decreased, and c-met expression increased progressively in more aggressive cell lines. Tissue microarray analysis revealed strong positive staining of tumour cells for syndecan-1 in 72%, E-cadherin in 67.8% and c-met in 48.6% of DCIS. E-cadherin expression was significantly associated with c-met and syndecan-1. Expression of c-met and syndecan-1 was significantly more frequent in the subgroup of patients with pure DCIS than in those with DCIS and a coexisting invasive carcinoma. Levels of c-met and syndecan-1 expression were associated with HER2 expression. Expression of c-met significantly correlated with expression of endothelin A and B receptors, vascular endothelial growth factor (VEGF)-A and fibroblast growth factor receptor-1, whereas E-cadherin expression correlated significantly with endothelin A receptor, VEGF-A and VEGF-C staining. CONCLUSION: Syndecan-1, E-cadherin and c-met constitute a marker signature associated with angiogenic and lymphangiogenic factors in DCIS. This coexpression may reflect a state of parallel activation of different signal transduction pathways, promoting tumour cell proliferation and angiogenesis. Our findings have implications for future therapeutic approaches in terms of a multiple target approach, which may be useful early in breast cancer progression

    Prognostic Factors In Breast Cancer. With Special Reference to Cyclins A, B1, D1 and E, MMP-1 and Decorin

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    Breast cancer is a highly heterogenous malignancy, which despite of the similar histological type shows different clinical behaviour and response to therapy. Prognostic factors are used to estimate the risk for recurrence and the likelihood of treatment effectiveness. Because breast cancer is one of the most common causes of cancer death in women worldwide, identification of new prognostic markers are needed to develop more specific and targeted therapies. Cancer is caused by uncontrolled cell proliferation. The cell cycle is controlled by specific proteins, which are known as cyclins. They function at important checkpoints by activating cyclin-dependent kinase enzymes. Overexpression of different cyclins has been linked to several cancer types and altered expression of cyclins A, B1, D1 and E has been associated with poor survival. Little is known about the combined expression of cyclins in relation to the tumour grade, breast cancer subtype and other known prognostic factors. In this study cyclins A, B1 and E were shown to correlate with histological grade, Ki-67 and HER2 expression. Overexpression of cyclin D1 correlated with receptor status and non-basal breast cancer suggesting that cyclin D1 might be a marker of good prognosis. Proteolysis in the surrounding tumour stroma is increased during cancer development. Matrix metalloproteinases (MMPs) are proteolytic enzymes that are capable of degrading extracellular matrix proteins. Increased expression and activation of several MMPs have been found in many cancers and MMPs appear to be important regulators of invasion and metastasis. In this study MMP-1 expression was analysed in breast cancer epithelial cells and in cancer associated stromal cells. MMP-1 expression by breast cancer epithelial cells was found to carry an independent prognostic value as did Ki-67 and bcl-2. The results suggest that in addition to stromal cells MMP-1 expression in tumour cells control breast cancer progression. Decorin is a small proteoglycan and an important component of the extracellular matrix. Decorin has been shown to inhibit growth of tumour cells and reduced decorin expression is associated with a poor prognosis in several cancer types. There has been some suspicion wheather different cancer cells express decorin. In this study decorin expression was shown to localize only in the cells of the original stroma, while breast cancer epithelial cells were negative for decorin expression. However, transduction of decorin in decorin-negative human breast cancer cells markedly modulated the growth pattern of these cells. This study provides evidence that targeted decorin transduction to breast cancer cells could be used as a novel adjuvant therapy in breast malignancies.Siirretty Doriast

    Application of morphometry, static DNA ploidy analysis, and steroid receptor expression in diagnosis and prognosis of Libyan breast cancer

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    The aim of this study was to describe the demographic, clinicopathological, biological and morphometric features of Libyan breast cancer patients. The supporting value of nuclear morphometry and static image cytometry in the sensitivity for detecting breast cancer in conventional fine-needle aspiration biopsies were estimated. The findings were compared with findings in breast cancer in Finland and Nigeria. In addation, the value of ER and PR were evaluated. There were 131 histological samples, 41 cytological samples, and demographic and clinicopathological data from 234 Libyan patients. The Libyan breast cancer is dominantly premenopausal and in this feature it is similar to breast cancer in sub-Saharan Africans, but clearly different from breast cancer in Europeans, whose cancers are dominantly postmenopausal in character. At presention most Libyan patients have locally advanced disease, which is associated with poor survival rates. Nuclear morphometry and image DNA cytometry agree with earlier published data in the Finnish population and indicate that nuclear size and DNA analysis of nuclear content can be used to increase the cytological sensitivity and specificity in doubtful breast lesions, particularly when free cell sampling method is used. Combination of the morphometric data with earlier free cell data gave the following diagnostic guidelines: Range of overlap in free cell samples: 55 μm2 -71 μm2. Cut-off values for diagnostic purposes: Mean nuclear area (MNA) >54 μm2 for 100% detection of malignant cases (specificity 84 %), MNA < 72 μm2 for 100% detection of benign cases (sensitivity 91%). Histomorphometry showed a significant correlation between the MNA and most clinicopathological features, with the strongest association observed for histological grade (p <0.0001). MNA seems to be a prognosticator in Libyan breast cancer (Pearson’s test r = - 0.29, p = 0.019), but at lower level of significance than in the European material. A corresponding relationship was not found in shape-related morphometric features. ER and PR staining scores were in correlation with the clinical stage (p= 0.017, and 0.015, respectively), and also associated with lymph node negative patients (p=0.03, p=0.05, respectively). Receptor-positive (HR+) patients had a better survival. The fraction of HR+ cases among Libyan breast cancers is about the same as the fraction of positive cases in European breast cancer. The study suggests that also weak staining (corresponding to as few as 1% positive cells) has prognostic value. The prognostic significance may be associated with the practice to use antihormonal therapy in HR+ cases. The low survival and advanced presentation is associated with active cell proliferation, atypical nuclear morphology and aneuploid nuclear DNA content in Libyan breast cancer patients. The findings support the idea that breast cancer is not one type of disease, but should probably be classified into premenopausal and post menopausal types.Morfometria, staattinen DNA sytometria, ja steroidireseptorit libyalaisen rintasyövän diagnostiikassa ja ennusteen arvioinnissa Väitöskirja kuvaa rintasyöpää sairastavien libyalaisten naisten elinoloja, ja heidän rintasyöpänsä kliinispatologisia, biologisia ja morfometrisia piirteitä. Tutkimuksessa arvioitiin, miten tumamorfometria ja staattinen DNA sytometriä lisäävät ohutneulabiopsian herkkyyttä löytää syöpäkasvain. Löydöksiä verrattiin suomalaisten ja nigerialaisten rintasyöpäpotilaiden tietoihin. Työssä arvioitiin myös steroidireseptorin merkitystä rintasyöpämateriaalissa. 131 histologista ja 41 sytologista näytettä analysoitiin, ja 234 libyalaisen potilaan kliinispatologiset ja väestötiedot tutkittiin. Libyalainen rintasyöpä on etupäässä premenopausaalista, ja eroaa siksi eurooppalaisesta rintasyövästä, joka on pääosin postmenopausaalista. Saharan eteläpuolinen rintasyöpä Afrikassa on myös selvästi premenopausaalista. Taudin toteamisvaiheessa useimmilla libyalaisilla naisilla oli paikallisesti levinnyt rintasyöpä johon liittyy huonompi ennuste kuin vain maitorauhasen sisäiseen syöpään. Tumamorfometrian ja DNA sytometrian tulokset ovat yhteneväisiä suomalaisesta rintasyöpämateriaalista julkaistujen tulosten kanssa. Menetelmiä voidaan käyttää lisäämään ohutneulabiopsiatutkimuksen herkkyyttä ja spesifisyyttä. Kun aikaisempien tutkimusten tulokset yhdistetään tässä tutkimuksessa havaittuihin, saadaan diagnostiikassa käytettäviksi tuloksiksi: hyvänlaatuisten ja rintasyöpäsolujen yhteinen kokoalue oli 55-71 neliömikrometriä. Kaikki syöpätapaukset löydettiin niiden näytteiden joukosta, joissa tumien alojen keskiarvo oli yli 54 neliömikrometriä. Tämä vastaa 100%:n herkkyyttä. Vastaava spesifisyys oli 84%. Kaikki hyvänlaatuiset näytteet sisältyivät tapauksiin, joissa tuman keskimääräinen ala oli alle 72 neliömikrometriä. Tällä alueella rintasyövän toteamisen herkkyys oli 91%. Rintasyöpäsolun keskimääräinen tuman pinta-ala oli suhteessa useimpiin ennusteellisiin kliinispatologisiin tietoihin. Vahvin korrelaatio oli suhteessa histologiseen erilaistumisasteeseen (gradus). Tilastollinen merkitsevyys ei kuitenkaan ollut libyalaisessa materiaalissa samaa luokkaa kuin aikaisemmin julkaistussa suomalaisessa materiaalissa. Kasvainsolun tuman muotoon liittyvillä tekijöillä ei ollut ennusteellista merkitystä. Steroidireseptorien värjäytyvyyttä arvioitiin histologisesti. Värjäytyvyydellä oli selvä yhteys kliiniseen levinneisyysasteeseen ja imusolmuke-etäpesäkkeiden esiintymiseen. Steroidireseptoripositiiviset syövät liittyivät pitempään keskimääräiseen eloonjäämisaikaan. Steroidireseptoripositiivisten potilaiden osuus libyalaisessa materiaalissa oli sama kuin suomalaisessa materiaalissa. Tutkimus osoitti, että myös heikko värjäytyminen oli ennusteellisesti merkitsevä. Reseptorien ennusteellinen merkitys voi liittyä siihen, että positiivisia potilaita hoidetaan antiestrogeenihoidolla. Rintasyövän heikompi ennuste Libyassa ja taudin levinneisyys diagnoosivaiheessa näyttää liittyvän lisääntyneeseen proliferaatioaktiivisuuteen, poikkeavaan tumarakenteeseen ja aneuploidiseen DNA pitoisuuteen. Löydökset tukevat ajatusta, että rintasyöpää ei välttämättä ole pidettävä yhtenäisenä biologisena tautina, vaan se voitaisiin ehkä jakaa premenopausaaliseen ja postmenopausaaliseen rintasyöpään.Siirretty Doriast

    Caveolin 1 is overexpressed and amplified in a subset of basal-like and metaplastic breast carcinomas: a morphologic, ultrastructural, immunohistochemical, and in situ hybridization analysis

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    The distribution and significance of caveolin 1 (CAV1) expression in different breast cell types and role in breast carcinogenesis remain poorly understood. Both tumor-suppressive and oncogenic roles have been proposed for this protein. The aims of this study were to characterize the distribution of CAV1 in normal breast, benign breast lesions, breast cancer precursors, and metaplastic breast carcinomas; to assess the prognostic significance of CAV1 expression in invasive breast carcinomas; and to define whether CAV1 gene amplification is the underlying genetic mechanism driving CAV1 overexpression in breast carcinomas. Purpose: The distribution and significance of caveolin 1 (CAV1) expression in different breast cell types and role in breast carcinogenesis remain poorly understood. Both tumor-suppressive and oncogenic roles have been proposed for this protein. The aims of this study were to characterize the distribution of CAV1 in normal breast, benign breast lesions, breast cancer precursors, and metaplastic breast carcinomas; to assess the prognostic significance of CAV1 expression in invasive breast carcinomas; and to define whether CAV1 gene amplification is the underlying genetic mechanism driving CAV1 overexpression in breast carcinomas. Experimental Design: CAV1 distribution in frozen and paraffin-embedded whole tissue sections of normal breast was evaluated using immunohistochemistry, immunofluorescence, and immunoelectron microscopy. CAV1 expression was immunohistochemically analyzed in benign lesions, breast cancer precursors, and metaplastic breast carcinomas and in a cohort of 245 invasive breast carcinomas from patients treated with surgery followed by anthracycline-based chemotherapy. In 25 cases, CAV1 gene amplification was assessed by chromogenic in situ hybridization. Results: In normal breast, CAV1 was expressed in myoepithelial cells, endothelial cells, and a subset of fibroblasts. Luminal epithelial cells showed negligible staining. CAV1 was expressed in 90% of 39 metaplastic breast carcinomas and in 9.4% of 245 invasive breast cancers. In the later cohort, CAV1 expression was significantly associated with ‘basal-like’ immunophenotype and with shorter disease-free and overall survival on univariate analysis. CAV1 gene amplification was found in 13% of cases with strong CAV1 expression. Conclusions: The concurrent CAV1 amplification and overexpression call into question its tumor-suppressive effects in basal-like breast carcinomas

    Breast Tumor Angiogenesis and Tumor-Associated Macrophages: Histopathologist's Perspective

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    Much progress has been made since the conceptualization of tumor angiogenesis—the induction of growth of new blood vessels by tumor—as a salient feature of clinically significant primary or metastatic cancers. From a practicing histopathologist's point of view, we appraise the application of this concept in breast cancer with particular reference to the evaluation of proangiogenic factors and the assessment of new microvessels in histopathological examination. Recently, much focus has also been centered on the active roles played by tumor-associated macrophages in relation to tumor angiogenesis. We review the literature; many data supporting this facet of tumor angiogenesis were derived from the breast cancer models. We scrutinize the large body of clinical evidence exploring the link between the tumor-associated macrophages and breast tumor angiogenesis and discuss particularly the methodology and limitations of incorporating such an assessment in histopathological examination
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