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

The cancer stem cell (CSC) hypothesis suggests that neoplastic clones are maintained exclusively by a rare fraction of cells with stem cell properties. Although the existence of CSCs in human leukaemia is established, little evidence exists for CSCs in solid tumours, except for breast cancer. Recently, we prospectively isolated a CD133+ cell subpopulation from human brain tumours that exhibited stem cell properties in vitro. However, the true measures of CSCs are their capacity for self renewal and exact recapitulation of the original tumour. Here we report the development of a xenograft assay that identified human brain tumour initiating cells that initiate tumours in vivo. Only the CD133+ brain tumour fraction contains cells that are capable of tumour initiation in NOD-SCID (non-obese diabetic, severe combined immunodeficient) mouse brains. Injection of as few as 100 CD133+ cells produced a tumour that could be serially transplanted and was a phenocopy of the patient's original tumour, whereas injection of 10(5) CD133- cells engrafted but did not cause a tumour. Thus, the identification of brain tumour initiating cells provides insights into human brain tumour pathogenesis, giving strong support for the CSC hypothesis as the basis for many solid tumours, and establishes a previously unidentified cellular target for more effective cancer therapies.
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PMID:Identification of human brain tumour initiating cells. 1554 78

The effects of HER-2/neu overexpression on the tumor microenvironment in an aggressive breast cancer xenograft model were investigated. These studies focused on tumors derived following the subcutaneous injection of MDA-MB-435/LCC6 cells transfected with human c-erbB2 (LCC6(HER-2)) into SCID-Rag2M mice. LCC6(HER-2) tumors were more viable (H&E-stained tumor sections) than isogenic vector control tumors (LCC6(Vector)). Correspondingly, a 2.7-fold increase in trypan blue-excluding cells (P = 0.00056) and a 4.8-fold increase in clonogenic cells (P = 0.00146) were noted in cell suspensions derived from disaggregated LCC6(HER-2) versus LCC6(Vector) tumors. Tumor sections stained with the antibody detecting 2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)-acetamide (EF5), a marker of hypoxia, showed a greater fraction of hypoxic tissue in LCC6(HER-2) tumors compared with control tumors. Flow cytometric analyses based on viable tumor cells (DNA content >/= 2N) in cell suspensions from disaggregated tumors confirmed that there were significantly more EF5-positive cells (i.e., hypoxic) in LCC6(HER-2) than in LCC6(Vector) tumors (16.41 +/- 8.1% and 5.96 +/- 4.1%, respectively; P = 0.0015). Protein levels of phosphorylated (Ser(536)) nuclear factor-kappaB p65 were significantly elevated in LCC6(HER-2) tumors (P = 0.00048), and a trend in increased hypoxia-inducible factor-1alpha protein levels was observed in LCC6(HER-2) compared with LCC6(Vector) tumors. Despite the substantial viable hypoxic cell fraction and a 1.7-fold increase of vascular endothelial growth factor protein (P = 0.05) in LCC6(HER-2) tumors, no significant differences were found (P > 0.05) between LCC6(HER-2) and LCC6(Vector) vasculature (CD31 staining and Hoechst 33342 perfusion). These results suggest that HER-2/neu overexpression may be linked with overall increased tumor viability and a significant increase in the population of viable hypoxic cells, which is not due to differences in tumor vascularization.
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PMID:HER-2/neu overexpression increases the viable hypoxic cell population within solid tumors without causing changes in tumor vascularization. 1556 77

Psychological distress reduces the efficacy of chemotherapy in breast cancer patients. The mechanism may be related to the altered neuronal or hormonal secretions during stress. Here, we reported that adrenaline, a hormone mediating the biological activities of stress, upregulates mdr1 gene expression in MCF-7 breast cancer cells via alpha(2)-adrenergic receptors in a dose-dependent manner. Mdr1 upregulation can be specifically inhibited by pretreatment with mdr1-siRNA. Consequently, adrenergic stimulation enhances the pump function of P-glycoprotein and confers resistance of MCF-7 cells to paclitaxel. In vivo, restraint stress increases mdr1 gene expression in the MCF-7 cancers that are inoculated subcutaneously into the SCID mice and provokes resistance to doxorubicin in the implanted tumors. The effect can be blocked by injection of yohimbine, an alpha(2)-adrenergic inhibitor, but not by metyrapone, a corticosterone synthesis blocker. Therefore, we conclude that breast cancers may develop resistance against chemotherapeutic drugs under psychological distress by over-expressing mdr1 via adrenergic stimulation.
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PMID:Psychological stress induces chemoresistance in breast cancer by upregulating mdr1. 1575 39

As more becomes known about the expression profiles of normal and cancerous cells, it should become possible to design antisense-based imaging agents for the early detection of cancer noninvasively. In this report, we rationally designed and synthesized three antisense and one sense hybrid PNA (peptide nucleic acid) to the unr mRNA that is highly overexpressed in a breast cancer cell line (MCF-7). The conjugates had a four-lysine tail at the carboxy terminus for cell permeation and a DOTA (1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid) chelating moiety at the amino terminal end for chelating (64)Cu for biodistribution and microPET imaging studies. Biodistribution of two (64)Cu-labeled conjugates with antisense and sense sequences (PNA50 and PNA50S) showed high uptake and long retention in kidney and low uptake and efficient clearance in blood and muscle in normal balb/c mice when administered intravenously or intraperitoneally. Intraperitoneal administration, however, gave a much slower release rate. MCF-7 tumors (100-320 mg) in CB-17 SCID mice were imaged with all four (64)Cu-labeled PNA conjugates by microPET, but the image contrast varied with different time points and different conjugates. Of the conjugates studied, (64)Cu-DOTA-Y-PNA50-K4 showed the best tumor image quality at all time points with a tumor/muscle ratio of 6.6 +/- 1.1 at 24 h postinjection, which is among the highest reported for radiolabeled oligonucleotides. Our work further strengthens the potential of antigene and antisense PNAs to be utilized as specific molecular probes for early detection of cancer and ultimately for patient specific radiotherapy.
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PMID:MicroPET imaging of MCF-7 tumors in mice via unr mRNA-targeted peptide nucleic acids. 1576 82

B7-H4 protein is expressed on the surface of a variety of immune cells and functions as a negative regulator of T cell responses. We independently identified B7-H4 (DD-O110) through a genomic effort to discover genes upregulated in tumors and here we describe a new functional role for B7-H4 protein in cancer. We show that B7-H4 mRNA and protein are overexpressed in human serous ovarian cancers and breast cancers with relatively little or no expression in normal tissues. B7-H4 protein is extensively glycosylated and displayed on the surface of tumor cells and we provide the first demonstration of a direct role for B7-H4 in promoting malignant transformation of epithelial cells. Overexpression of B7-H4 in a human ovarian cancer cell line with little endogenous B7-H4 expression increased tumor formation in SCID mice. Whereas overexpression of B7-H4 protected epithelial cells from anoikis, siRNA-mediated knockdown of B7-H4 mRNA and protein expression in a breast cancer cell line increased caspase activity and apoptosis. The restricted normal tissue distribution of B7-H4, its overexpression in a majority of breast and ovarian cancers and functional activity in transformation validate this cell surface protein as a new target for therapeutic intervention. A therapeutic antibody strategy aimed at B7-H4 could offer an exciting opportunity to inhibit the growth and progression of human ovarian and breast cancers.
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PMID:The immunomodulatory protein B7-H4 is overexpressed in breast and ovarian cancers and promotes epithelial cell transformation. 1587 39

Breast cancer-initiating cells have been recently identified in breast carcinoma as CD44+/CD24(-/low) cells, which exclusively retain tumorigenic activity and display stem cell-like properties. However, at present, direct evidence that breast cancer-initiating cells can be propagated in vitro is still lacking. We report here the isolation and in vitro propagation of breast cancer-initiating cells from three breast cancer lesions and from an established breast carcinoma cell line. Our breast carcinoma-derived cultures encompassed undifferentiated cells capable of self-renewal, extensive proliferation as clonal nonadherent spherical clusters, and differentiation along different mammary epithelial lineages (ductal and myoepithelial). Interestingly, cultured cells were CD44+/CD24- and Cx43-, overexpressed neoangiogenic and cytoprotective factors, expressed the putative stem cell marker Oct-4, and gave rise to new tumors when as few as 10(3) cells were injected into the mammary fat pad of SCID mice. Long-term cultures of breast tumorigenic cells with stem/progenitor cell properties represent a suitable in vitro model to study breast cancer-initiating cells and to develop therapeutic strategies aimed at eradicating the tumorigenic subpopulation within breast cancer.
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PMID:Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. 1599 20

Sialyl-Tn is a carbohydrate antigen overexpressed in several epithelial cancers, including breast cancer, and usually associated with poor prognosis. Sialyl-Tn is synthesized by a CMP-Neu5Ac:GalNAcalpha2,6-sialyltransferase: CMP-Neu5Ac: R-GalNAcalpha1-O-Ser/Thr alpha2,6-sialyltransferase (EC 2.4.99.3) (ST6GalNAc I), which transfers a sialic acid residue in alpha2,6-linkage to the GalNAcalpha1-O-Ser/Thr structure. However, established breast cancer cell lines express neither ST6GalNAc I nor sialyl-Tn. We have previously shown that stable transfection of MDA-MB-231, a human breast cancer cell line, with ST6GalNAc I cDNA induces sialyl-Tn antigen (STn) expression. We report here the modifications of the O-glycosylation pattern of a MUC1-related recombinant protein secreted by MDA-MB-231 sialyl-Tn positive cells. We also show that sialyl-Tn expression and concomitant changes in the overall O-glycan profiles induce a decrease of adhesion and an increase of migration of MDA-MB-231. Moreover, STn positive clones exhibit an increased tumour growth in severe combined immunodeficiency (SCID) mice. These observations suggest that modification of the O-glycosylation pattern induced by ST6GalNAc I expression are sufficient to enhance the tumourigenicity of MDA-MB-231 breast cancer cells.
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PMID:ST6GalNAc I expression in MDA-MB-231 breast cancer cells greatly modifies their O-glycosylation pattern and enhances their tumourigenicity. 1613 58

We analyzed the differential gene expression between variants of MDA-MB-435 human breast cancer cell line that share an identical genetic background but have different metastatic ability. The major histocompatibility complex class II was found down-regulated in highly metastatic cells and correlated with MHC transactivator (CIITA) expression. Constitutive CIITA expression observed in poorly metastatic is driven by promoters III and IV of CIITA gene. Conversely, both promoters were ineffective in highly metastatic cells. The MHC class II and CIITA expression was restored in these cells upon stimulation with IFNgamma or by the treatment with a hypomethylating agent. Both treatments induced USF-1 and IRF binding complexes to promoter IV but only IFNgamma induced the binding of 435-Lung2 nuclear proteins to an ARE-1 site at the promoter III. Neither Southern blot nor bisulfite sequencing of promoter IV demonstrated strong hypermethylation of this promoter at the IFNgamma-responsive elements such as GAS, E-box or IRF-1. We suggest that partial or hemimethylation of promoter IV is sufficient to silence the CIITA expression in highly metastatic cells and that this epigenetic mechanism is responsible for the lack of MHC-II expression. Forced CIITA expression restored the MHC-II antigen expression in 435-Lung2 cells and abrogates spontaneous lung metastasis in both SCID and nude mice but also affected the tumorigenicity in nude mice. The increase in NK cell infiltration in nude mice bearing CIITA-tumors correlated with sign of tumor cell apoptosis and the increase in the number of NK cells in the spleens, suggesting that NK cells might be responsible for the observed antitumor activity.
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PMID:Differential expression of MHC class II molecules in highly metastatic breast cancer cells is mediated by the regulation of the CIITA transcription Implication of CIITA in tumor and metastasis development. 1634 78

CD24 is a small, heavily glycosylated cell-surface protein which is linked to the membrane via a glycosyl-phosphatidylinositol (GPI-) anchor and therefore localizes in lipid rafts. CD24 is widely used as a cell-lineage marker for hematopoietic cells. CD24 is also expressed on a variety of human carcinomas, including epithelial ovarian, breast, prostate, colon and lung cancer and has been linked to poor prognosis. Except for its role as a ligand for P-selectin on carcinoma and myeloid cells, a specific function for CD24 has not been determined. Here we show that CD24 affects the function of the chemokine receptor CXCR4. Using isolated CD19-positive bone marrow B cells from CD24-knockout mice and CD24-/- pre-B lymphocytic cell lines, we demonstrate that CD24 expression reduces SDF-1-mediated cell migration and signalling via CXCR4. We observed that the loss of CD24 augmented cellular cholesterol levels and enhanced CXCR4 lipid raft association. Altered chemotactic migration and raft residence was also observed in MDA-MB-231 breast cancer cells expressing high and low levels of CD24 and CXCR4 receptor. MDA-MB-231 cells expressing low levels of CD24 also showed enhanced tumour formation in NOD/SCID mice compared with cells overexpressing CD24. These results demonstrate a novel role for CD24 as a regulator of CXCR4 function that could be relevant for breast cancer growth and metastasis.
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PMID:CD24 affects CXCR4 function in pre-B lymphocytes and breast carcinoma cells. 1639 Aug 67

Natural killer (NK) cell is an important component of the innate immune system and plays a central role in host defense against tumor and virus-infected cells. This review briefly summarizes the role of murine NK cells in tumor growth and metastasis of breast cancer cells in severe combined immunodeficiency (SCID) mice. Conventional SCID and NOD-SCID strains have been used to study for xenotransplantion of human tumors. SCID mice models of cancer mimic human diseases and have provided valuable information. However, these mice strains have some residual immunity such as NK cells that somewhat limit post-transplantation growth and metastasis of human xenografts. In contrast, NOD/SCID/gammac(null) (NOG) mice without common gamma-chain inoculated with breast cancer cells were most efficient in the formation of a large tumor and metastasis. NOG mouse strain without NK activity appears to be more promising as tool for xenotransplantion of human cancer. This new xenotransplant model is relevant and can be recommended for use in clarifying the mechanism of growth of cancer cells as well as for developing new therapeutic strategies against cancer.
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PMID:Natural killer cells in breast cancer cell growth and metastasis in SCID mice. 1650 13


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