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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The immunohistochemical expression of the extracellular matrix (ECM) components tenascin (TN), fibronectin (FN), collagen type IV (Coll) and laminin (LN), and their possible relationships were studied in a series of 134 operable breast cancer cases. Their expression was also compared with the expression of the proteolytic enzyme cathepsin D (CD), the adhesion molecule CD44 standard form (CD44s) and other known factors to clarify the prognostic value and role of these molecules in tumour progression and metastasis. TN expression in the tumour stroma was positively correlated with tumour grade and size, CD44s expression, tumour and stromal CD expression as well as with FN, laminin and Coll expression in the same areas. TN expression was inverse correlated with ER status. Its expression at the invasion front was only positively correlated with the lymph node status. Survival analysis showed an increased mortality risk associated with high levels of TN expression. In multivariate analysis, among the ECM proteins, only TN expression was independently correlated with patients' survival. FN expression was positively correlated with lymph node involvement, with the proliferation-associated index Ki-67 and stromal CD expression. Survival analysis showed an increased mortality risk associated with a high level of FN expression. Coll expression was positively correlated with the tumour size and LN expression. An inverse relationship of Coll expression with ER and PgR receptor status was also found. LN expression was positively correlated with tumour and stromal CD expression, with the proliferation-associated index Ki-67 and inversely with ER receptor status. The observed alterations in the expression of ECM proteins in breast cancer tissue and their correlations with the proteolytic enzyme CD and the adhesion molecule CD44s, suggest an involvement in cancer progression. In addition, overexpression of stromal TN and FN seems to have negative prognostic value in breast cancer patients.
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PMID:Immunohistochemical expression of extracellular matrix components tenascin, fibronectin, collagen type IV and laminin in breast cancer: their prognostic value and role in tumour invasion and progression. 1246 Jul 79

Breast cancer is the most common malignancy in United States women, accounting for >40,000 deaths each year. These breast tumors are comprised of phenotypically diverse populations of breast cancer cells. Using a model in which human breast cancer cells were grown in immunocompromised mice, we found that only a minority of breast cancer cells had the ability to form new tumors. We were able to distinguish the tumorigenic (tumor initiating) from the nontumorigenic cancer cells based on cell surface marker expression. We prospectively identified and isolated the tumorigenic cells as CD44(+)CD24(-/low)Lineage(-) in eight of nine patients. As few as 100 cells with this phenotype were able to form tumors in mice, whereas tens of thousands of cells with alternate phenotypes failed to form tumors. The tumorigenic subpopulation could be serially passaged: each time cells within this population generated new tumors containing additional CD44(+)CD24(-/low)Lineage(-) tumorigenic cells as well as the phenotypically diverse mixed populations of nontumorigenic cells present in the initial tumor. The ability to prospectively identify tumorigenic cancer cells will facilitate the elucidation of pathways that regulate their growth and survival. Furthermore, because these cells drive tumor development, strategies designed to target this population may lead to more effective therapies.
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PMID:Prospective identification of tumorigenic breast cancer cells. 2042 52

Breast ductal carcinoma in situ is an intraductal proliferation of malignant epithelial cells that diffuse within the ductal system without stromal invasion. Our finding that a subset of these tumors express CD31/platelet endothelial cell adhesion molecule-1 suggests that breast cancer represents an informative model for studying the involvement of the molecule in the morphogenesis, differentiation, and diffusion of this disease. Transfection of CD31 in MDA-MB-231 cells caused reduction in growth, loss of CD44, and acquisition of a ductal morphology. The same effects were maintained in vivo, in which CD31(+) tumors grew with in situ-like aspects, papillary differentiation, and a secretory phenotype. CD44 was down-modulated, with the CD31(+) cells blocked in the G(1) phase. The morphology was highly similar to what was observed in some human CD31(+) ductal carcinomas in situ. MDA-MB-231 mock cells grew in solid sheets, lacking stromal material, and displaying high levels of CD44 and proliferation. CD31(+) cells acquired motility characteristics in in vitro assays, a finding confirmed in vivo by the diffusion of human tumor cells throughout the normal ducts residual in the murine mammary gland. In conclusion, CD31 expression reverts the undifferentiated morphology and aggressive behavior of MDA-MB-231 cells, indicating its active role in the morphogenesis of breast ductal in situ carcinomas.
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PMID:Role of CD31/platelet endothelial cell adhesion molecule-1 expression in in vitro and in vivo growth and differentiation of human breast cancer cells. 1265 8

In this study we have examined CD44 (a hyaluronan (HA) receptor) interaction with a RhoA-specific guanine nucleotide exchange factor (p115RhoGEF) in human metastatic breast tumor cells (MDA-MB-231 cell line). Immunoprecipitation and immunoblot analyses indicate that both CD44 and p115RhoGEF are expressed in MDA-MB-231 cells and that these two proteins are physically associated as a complex in vivo. The binding of HA to MDA-MB-231 cells stimulates p115RhoGEF-mediated RhoA signaling and Rho kinase (ROK) activity, which, in turn, increases serine/threonine phosphorylation of the adaptor protein, Gab-1 (Grb2-associated binder-1). Phosphorylated Gab-1 promotes PI 3-kinase recruitment to CD44v3. Subsequently, PI 3-kinase is activated (in particular, alpha, beta, gamma forms but not the delta form of the p110 catalytic subunit), AKT signaling occurs, the cytokine (macrophage-colony stimulating factor (M-CSF)) is produced, and tumor cell-specific phenotypes (e.g. tumor cell growth, survival and invasion) are up-regulated. Our results also demonstrate that HA/CD44-mediated oncogenic events (e.g. AKT activation, M-CSF production and breast tumor cell-specific phenotypes) can be effectively blocked by a PI 3-kinase inhibitor (LY294002). Finally, we have found that overexpression of a dominant-negative form of ROK (by transfection of MBA-MD-231 cells with the Rho-binding domain cDNA of ROK) not only inhibits HA/CD44-mediated RhoA-ROK activation and Gab-1 phosphorylation but also down-regulates oncogenic signaling events (e.g. Gab-1.PI 3-kinase-CD44v3 association, PI 3-kinase-mediated AKT activation, and M-CSF production) and tumor cell behaviors (e.g. cell growth, survival, and invasion). Taken together, these findings strongly suggest that CD44 interaction with p115RhoGEF and ROK plays a pivotal role in promoting Gab-1 phosphorylation leading to Gab-1.PI 3-kinase membrane localization, AKT signaling, and cytokine (M-CSF) production during HA-mediated breast cancer progression.
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PMID:Hyaluronan-mediated CD44 interaction with RhoGEF and Rho kinase promotes Grb2-associated binder-1 phosphorylation and phosphatidylinositol 3-kinase signaling leading to cytokine (macrophage-colony stimulating factor) production and breast tumor progression. 1274 84

Altered gene expression during breast tumour progression can occur through alternative splicing of mRNAs. The SR proteins have been identified as important factors in RNA splicing and in the incorporation of alternative exons in experimental systems. We have studied SR protein expression by western blot in human breast cell lines and in a cohort of 101 invasive breast tumours to examine the relationship with alternatively spliced isoforms of the CD44 gene. Multiple SR proteins (SR75, 55, 40, 30) were expressed in most cell lines and tumours, and their relative expression was independent of grade, size, or nodal status. Higher relative expression of SR55 protein was associated with an altered pattern of CD44 variants incorporating exon v7 (p = 0.047) as determined by reverse transcription-polymerase chain reaction (RT-PCR) and Southern blot analysis. Nevertheless, transient transfection of MCF7 and HBL100 breast cell lines with SR55 had no direct effect on the expression of CD44 v7 variant expression. We conclude that while SR proteins may be important and necessary factors in mRNA splicing, other factors are also necessary to influence the regulation of alternatively spliced isoforms of CD44.
Breast Cancer Res Treat 2003 May
PMID:SR protein expression and CD44 splicing pattern in human breast tumours. 1277 84

For cancer metastasis, tumor cells present in the circulation must first adhere to the endothelium. Integrins play a central role in leukocyte adhesion to the endothelium and subsequent migration into tissues. The majority of tumor cells derived from solid cancers, including breast cancer, do not express integrins. We investigated the mechanisms of adhesion and transendothelial migration of cancer cells using breast carcinoma cell lines. Our results showed the following features of breast cancer cells: (1) HGF stimulated breast cancer cells by up-regulating CD44 expression in a concentration-dependent manner. (2) the maximum level of HGF-induced CD44 up-regulation on breast cancer cell lines occurred within 3 h. (3) HGF-induced up-regulation of CD44 was mediated by the tyrosine kinase signaling pathway. (4) HGF induced CD44-mediated adhesion of tumor cell lines to bone marrow-derived endothelial cells. (5) HGF did not change rolling of breast cancer cell lines on bone marrow-derived endothelial cells, but enhanced firm adhesion of cancer cells on endothelial cells under shear stress conditions. (6) HGF increased transendothelial migration of cancer cells. Our results indicate that HGF stimulates CD44-mediated adhesion of breast cancer cells to bone marrow-derived endothelial cells, which subsequently results in transendothelial migration of tumor cells. These results suggest that CD44 may confer the metastatic properties of breast cancer cells and, therefore, could be used as a target in future molecular cancer therapy.
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PMID:Hepatocyte growth factor enhances adhesion of breast cancer cells to endothelial cells in vitro through up-regulation of CD44. 1287 70

Tumors expressing a high level of certain types of tumor-associated carbohydrate antigens (TACAs) exhibit greater metastasis and progression than those expressing low level of TACAs, as reflected in decreased patient survival rate. Well-documented examples of such TACAs are: (i) H/Le(y)/Le(a) in primary non-small cell lung carcinoma; (ii) sialyl-Le(x) (SLe(x)) and sialyl-Le(a) (SLe(a)) in various types of cancer; (iii) Tn and sialyl-Tn in colorectal, lung, breast, and many other cancers; (iv) GM2, GD2, and GD3 gangliosides in neuroectodermal tumors (melanoma and neuroblastoma); (v) globo-H in breast, ovarian, and prostate cancer; (vi) disialylgalactosylgloboside in renal cell carcinoma. Some glycosylations and TACAs suppress invasiveness and metastatic potential. Well-documented examples are: (i) blood group A antigen in primary lung carcinoma; (ii) bisecting beta1 --> 4GlcNAc of N-linked structure in melanoma and other cancers; (iii) galactosylgloboside (GalGb4) in seminoma. The biochemical mechanisms by which the above glycosylation changes promote or suppress tumor metastasis and invasion are mostly unknown. A few exceptional cases in which we have some knowledge are: (i) SLe(x) and SLe(a) function as E-selectin epitopes promoting tumor cell interaction with endothelial cells; (ii) some tumor cells interact through binding of TACA to specific proteins other than selectin, or to specific carbohydrate expressed on endothelial cells or other target cells (carbohydrate-carbohydrate interaction); (iii) functional modification of adhesive receptor (integrin, cadherin, CD44) by glycosylation. So far, a few successful cases of anti-cancer vaccine in clinical trials have been reported, employing TACAs whose expression enhances malignancy. Examples are STn for suppression of breast cancer, GM2 and GD3 for melanoma, and globo-H for prostate cancer. Vaccine development canbe extended using other TACAs, with the following criteria for success: (i) the antigen is expressed highly on tumor cells; (ii) high antibody production depending on two factors: (a) clustering of antigen used in vaccine; (b) choice of appropriate carrier protein or lipid; (iii) high T cell response depending on choice of appropriate carrier protein or lipid; (iv) expression of the same antigen in normal epithelial tissues (e.g., renal, intestinal, colorectal) may not pose a major obstacle, i.e., these tissues are not damaged during immune response. Idiotypic anti-carbohydrate antibodies that mimic the surface profile of carbohydrate antigens, when administered to patients, elicit anti-carbohydrate antibody response, thus providing an effect similar to that of TACAs for suppression of tumor progression. An extension of this idea is the use of peptide mimetics of TACAs, based on phage display random peptide library. Although examples are so far highly limited, use of such "mimotopes" as immunogens may overcome the weak immunogenicity of TACAs in general.
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PMID:Tumor-associated carbohydrate antigens defining tumor malignancy: basis for development of anti-cancer vaccines. 1453 9

BRCA1 is an important susceptibility gene for breast cancer, which confers substantial lifetime risks of breast cancer, particularly in the pre-menopausal age group. Typically, carriers of BRCA1 mutations develop breast tumours that grow rapidly and are high grade and oestrogen receptor negative. They also possess a basal epithelial phenotype, as defined by cytokeratin expression, that is not present in most breast cancers. It has recently been proposed that the adult breast stem cell expresses only basal keratins. Others have indicated a CD44 positive, CD24 negative phenotype for breast cancer stem cells. In this paper, I argue that the biology of human BRCA1 and its rodent homologues and the clinicopathological features of breast cancer related to BRCA1 support the notion that one of the key functions of BRCA1 is to act as a stem cell regulator. This has implications for the management of carriers of mutations of BRCA1, in part because support for the role of BRCA1 as a stem cell regulator would emphasise the distinct nature of breast cancer related to BRCA1.
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PMID:BRCA1 functions as a breast stem cell regulator. 1472 16

With the objective of discovering novel putative intervention sites for anticancer therapy, we compared transcriptional profiles of breast cancer, lung squamous cell cancer (LSCC), lung adenocarcinoma (LAC), and renal cell cancer (RCC). Each of these tumor types still needs improvement in medical treatment. Our intention was to search for genes not only highly expressed in the majority of patient samples but which also exhibit very low or even absence of expression in a comprehensive panel of 16 critical (vital) normal tissues. To achieve this goal, we combined two powerful technologies, PCR-based cDNA subtraction and cDNA microarrays. Seven subtractive libraries consisting of approximately 9250 clones were established and enriched for tumor-specific transcripts. These clones, together with approximately 1750 additional tumor-relevant genes, were used for cDNA microarray preparation. Hybridizations were performed using a pool of 16 critical normal tissues as a reference in all experiments. In total, we analyzed 20 samples of breast cancer, 11 of LSCC, 11 of LAC, and 8 of RCC. To select for genes with low or even no expression in normal tissues, expression profiles of 22 different normal tissues were additionally analyzed. Importantly, this tissue-wide expression profiling allowed us to eliminate genes, which exhibit also high expression in normal tissues. Similarly, expression signatures of genes, which are derived from infiltrating cells of the immune system, were eliminated as well. Cluster analysis resulted in the identification of 527 expressed sequence tags specifically up-regulated in these tumors. Gene-wise hierarchical clustering of these clones clearly separated the different tumor types with RCC exhibiting the most homogeneous and LAC the most diverse expression profile. In addition to already known tumor-associated genes, the majority of identified genes have not yet been brought into context with tumorigenesis such as genes involved in bone matrix mineralization (OSN, OPN, and OSF-2) in lung, breast, and kidney cancer or genes controlling Ca(2+) homeostasis (RCN1,CALCA, S100 protein family). EGLN3, which recently has been shown to be involved in regulation of hypoxia-inducible factor, was found to be highly up-regulated in all RCCs and in half of the LSCCs analyzed. Furthermore, 42 genes, the expression level of which correlated with the overall survival of breast cancer patients, were identified. The gene dendogram clearly separates two groups of genes, those up-regulated such as cyclin B1, TGF-beta 3, B-Myb, Erg2, VCAM-1, and CD44 and those down-regulated such as MIG-6, Esp15, and CAK in patients with short survival time.
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PMID:Tissue-wide expression profiling using cDNA subtraction and microarrays to identify tumor-specific genes. 1487 11

CD44-protein and its isoforms are the multifunctional cell adhesion molecules participating in cell-cell and cell-matrix interactions. In this study we estimated the frequency of CD44-expression as well as two of its variants (CD44v3 and CD44v5) in female breast cancer. Among 75 breast carcinomas studied, 23 (44.2%) presented strong membrane reaction with monoclonal antibody against antigen CD44. The immunocytochemical reaction to CD44v3 and CD44v5 were observed in 16 (21.3%) and 50 (66.75%) cases, respectively. The presence of CD44v3 antigen on the surface of breast cancer cells significantly correlated with ER expression (0.0430) and the lack of p53 protein (p=0.0252), and also with the percentage of T cells in the total population of lymphocytes infiltrating the primary tumor (TILs) (p=0.0248). What is more important, the reaction to CDv3 significantly correlated with the presence of metastases to the lymph nodes (p=0.0385).
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PMID:The role of CD44v3 expression in female breast carcinomas. 1499 92


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