Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have characterized the LCC15-MB cell line which was recently derived from a breast carcinoma metastasis resected from the femur of a 29-year-old woman. LCC15-MB cells are vimentin (VIM) positive, exhibit a stellate morphology in routine cell culture, and form penetrating colonies when embedded in three-dimensional gels of Matrigel or fibrillar collagen. They show high levels of activity in the Boyden chamber chemomigration and chemoinvasion assays, and like other invasive human breast cancer (HBC) cell lines, LCC15-MB cells activate matrix-metalloproteinase-2 in response to treatment with concanavalin A. In addition, these cells are tumorigenic when implanted subcutaneously in nude mice and recolonize bone after arterial injection. Interestingly, both the primary lesion and the bone metastasis from which LCC15-MB were derived, as well as the resultant cell line, abundantly express the bone matrix protein osteopontin (OPN). OPN is also expressed by the highly metastatic MDA-MB-435 cells, but not other invasive or noninvasive HBC cell lines. Expression of OPN is retained in the subcutaneous xenograft and intraosseous metastases of LCC15-MB as detected by immunohistochemistry. Both VIM and OPN expression have been associated with breast cancer invasion and metastasis, and their expression by the LCC15-MB cell line is consistent with its derivation from a highly aggressive breast cancer. These cells provide a useful model for studying molecular mechanisms important for breast cancer metastasis to bone and, in particular, the implication(s) of OPN and VIM expression in this process.
 ...
PMID:The LCC15-MB human breast cancer cell line expresses osteopontin and exhibits an invasive and metastatic phenotype. 963 69

The aim of this study was to examine the cellular distribution of osteopontin (OPN) protein [by immunohistochemical (IHC) analysis] and mRNA [by in situ hybridization (ISH)] in the primary tumors of lymph node negative (LNN) breast cancer patients and to determine whether the level of immunodetectable OPN may be associated with tumor aggressiveness. We examined OPN levels in tumors from 154 patients with LNN breast cancer who were followed for a median of 7 years (range 1.7-16.3 years). IHC staining for OPN was seen in tumor infiltrating macrophages and lymphocytes in 70% of these tumors, and in the carcinoma cells themselves in 26%. ISH was performed to determine cellular distribution of OPN mRNA expression in sections from selected tumors. OPN mRNA was detected in groups of tumor cells, individual tumor cells and tumor infiltrating macrophages and lymphocytes. Matched sections showed that some tumor cells with IHC staining for OPN protein were also positive for OPN mRNA by ISH, in contrast with previous studies which have shown OPN mRNA expression only in tumor infiltrating inflammatory cells. Our results thus indicate that OPN protein can be produced by breast cancer cells in vivo and suggest that it may also be taken up from the environment (i.e., secreted by inflammatory cells or other tumor cells). Tumor cell IHC staining intensity was then assessed using a semiquantitative scoring system. Univariate analysis showed tumor cell OPN positivity above an optimized cutpoint to be significantly associated with decreased disease-free survival (DFS) and overall survival (OS). The results of this pilot study thus suggest that the ability of breast cancer cells to either synthesize OPN or to bind and sequester OPN from the microenvironment may be associated with tumor aggressiveness and poor prognosis.
 ...
PMID:Osteopontin expression in a group of lymph node negative breast cancer patients. 976 Nov 20

Osteopontin (OPN) is a secreted, integrin-binding phosphoprotein that has been implicated in both normal and pathological processes; qualitative increases in OPN blood levels have been reported in a small number of patients with metastatic tumors of various kinds. We measured plasma OPN levels in 70 women with known metastatic breast carcinoma, 44 patient controls who were on follow-up after completion of adjuvant treatment for early breast cancer, and 35 normal volunteers. The median plasma OPN of patients with metastatic disease was 142 microgram/liter (range, 38-1312 microgram/liter) and was significantly different (P < 0.0001, Mann Whitney U test) from both control groups (medians, 60 and 47 microgram/liter; ranges, 15-117 and 22-122 microgram/liter). Furthermore, we found that increasing plasma OPN is associated with shorter survival (P < 0.001) when patients were grouped in terciles for plasma OPN. This was also demonstrated when using a Cox proportional hazards model. Median plasma OPN levels were significantly increased for three or more sites of involvement (median, 232 microgram/liter; n = 13) versus 1 or 2 metastatic sites (medians, 129 and 130 microgram/liter; n = 29 and 28, respectively). Plasma OPN levels were correlated with other biochemical markers related to the extent of disease, such as serum alkaline phosphatase, aspartate succinate aminotransaminase, and albumin (r = 0.81, 0.62, and -0.56, respectively; all P < 0.001). This study demonstrates a statistically significant elevation in plasma OPN in the majority ( approximately 70%) of a large series of patients with metastatic breast cancer when compared (95th percentile) to healthy women or patients who had completed adjuvant treatment for early-stage breast cancer. Furthermore, this is the first study to demonstrate that higher OPN levels in patients with metastatic breast cancer may be associated with an increased number of involved sites and decreased survival.
 ...
PMID:Elevated plasma osteopontin in metastatic breast cancer associated with increased tumor burden and decreased survival. 981 27

MCF-7 breast cancer cells stably transfected with protein kinase C-alpha (MCF-7-PKC-alpha cells) show anchorage-independent growth and exhibit increased tumorigenicity in nude mice. Since integrins are involved in tumor growth and metastatic spread, we investigated whether integrin expression is differentially regulated in MCF-7-PKC-alpha cells. Fluorescence-activated cell sorting revealed that alphavbeta3 is highly expressed on MCF-7-PKC-alpha cells, but is undetectable on MCF-7V cells (MCF-7 cells transfected with vector only). In contrast, MCF-7-PKC-alpha cells have reduced expression of alphavbeta5. Blocking experiments with antibodies to alphavbeta3 and alphavbeta5 revealed that these receptors are used by MCF-7-PKC-alpha cells to adhere primarily to vitronectin and osteopontin. Consistent with heterodimer expression, MCF-7-PKC-alpha cells express increased beta3 and decreased beta5 on their surface. Surface expression of alphav on MCF-7-PKC-alpha cells is unchanged. Western blotting, Northern analysis, and nuclear run-on assays indicated that post-translational mechanisms increase the surface expression of beta3 on MCF-7-PKC-alpha cells. In contrast, reduced beta5 transcription diminishes beta5 surface expression on MCF-7-PKC-alpha cells. These results indicate that overexpression of PKC-alpha in MCF-7 cells alters beta5 and beta3 expression by transcriptional and post-translational mechanisms, respectively, resulting in altered heterodimer expression. These findings suggest that the increased metastatic capacity of tumor cells with elevated protein kinase C levels may result, in part, from modulation of integrin expression.
 ...
PMID:Overexpression of protein kinase C-alpha in MCF-7 breast cancer cells results in differential regulation and expression of alphavbeta3 and alphavbeta5. 1037 5

Bone sialoprotein (BSP) and osteopontin (OPN) are secreted glycoproteins with a conserved Arg-Gly-Asp (RGD) integrin-binding motif and are expressed predominantly in bone. The RGD tripeptide is commonly present in extracellular attachment proteins and has been shown to mediate the attachment of osteosarcoma cells and osteoclasts. To determine the origin and incidence of BSP and OPN mRNA expression in primary tumor, a cohort of archival, primary invasive breast carcinoma specimens was analyzed. BSP transcripts were detected in 65% and OPN transcripts in 77% of breast cancers examined. In general, BSP and OPN transcripts were detected in both invasive and in situ carcinoma components. The transcripts were not detected in surrounding stromal cells or in peritumoral macrophages. Despite its abundance in carcinomas, BSP expression was not detected in a panel of 11 human breast cancer cell lines (MCF-7, T47D, SK-Br-3, MDA-MB-453, MDA-MB-231, MDA-MB-436, BT549, MCF-7ADR, Hs578T, MDA-MB-435, and LCC15-MB) and OPN expression was detected only in two of these (MDA-MB-435 and LCC15-MB). To examine the possibility that expression of these genes was down-regulated in cell culture, several cell lines were grown as nude mouse xenografts in vivo; however, these tumors also failed to express BSP. OPN expression was identified in all cell lines grown as nude mouse xenografts. Our data suggest that in human primary breast tumors, the origin of BSP and OPN mRNA is predominantly the breast cancer cells and that expression of these transcripts is influenced by the tumor environment.
 ...
PMID:Tumor cells are the source of osteopontin and bone sialoprotein expression in human breast cancer. 1041 27

Osteopontin (OPN) has been associated with enhanced malignancy in breast cancer, but its functional role in this disease is poorly understood. To study the effect of OPN on cellular invasiveness, basal OPN expression was first assessed in members of a progression series of human mammary epithelial cell lines (21PT: immortalized, non-tumorigenic; 21NT: weakly tumorigenic; 21MT-1: tumorigenic, weakly metastatic; MDA-MB-435 cells: tumorigenic, highly metastatic). The two lines which expressed lowest basal levels of OPN (21PT, 21NT) were then examined for up-regulation of invasive behavior in response to exogenous or transfected (endogenous) OPN. Both 21PT and 21NT showed increased invasiveness through Matrigel when human recombinant (hr)OPN was added to the lower chamber of transwells. Both also showed a cell migration response to hrOPN. Populations of 21PT and 21NT cells stably transfected with an OPN-expression vector showed higher levels of cell invasiness than control vector transfectants. Examination of transfectants for mRNA of a number of secreted proteases showed that only urokinase-type plasminogen activator (uPA) expression was closely associated with OPN expression and cellular invasiveness. Treatment of the parental 21PT and 21NT cells with exogenous hrOPN resulted in increased uPA mRNA expression and increased urokinase activity of the conditioned media. Both increased cell migration and induction of uPA expression are thus potential mechanisms of increased invasiness of breast epithelial cells in response to OPN.
 ...
PMID:Osteopontin induces increased invasiveness and plasminogen activator expression of human mammary epithelial cells. 1043 36

Metastatic cancer cells, like trophoblasts of the developing placenta, are invasive and must escape immune surveillance to survive. Complement has long been thought to play a significant role in the tumor surveillance mechanism. Bone sialoprotein (BSP) and osteopontin (OPN, ETA-1) are expressed by trophoblasts and are strongly up-regulated by many tumors. Indeed, BSP has been shown to be a positive indicator of the invasive potential of some tumors. In this report, we show that BSP and OPN form rapid and tight complexes with complement Factor H. Besides its key role in regulating complement-mediated cell lysis, Factor H also appears to play a role when "hijacked" by invading organisms in enabling cellular evasion of complement. We have investigated whether BSP and OPN may play a similar role in tumor cell complement evasion by testing to see whether these glycoproteins could promote tumor cell survival. Recombinant OPN and BSP can protect murine erythroleukemia cells from attack by human complement as well as human MCF-7 breast cancer cells and U-266 myeloma cells from attack by guinea pig complement. The mechanism of this gain of function by tumor cell expression of BSP or OPN has been defined using specific peptides and antibodies to block BSP and OPN protective activity. The expression of BSP and OPN in tumor cells provides a selective advantage for survival via initial binding to alpha(V)beta(3) integrin (both) or CD44 (OPN) on the cell surface, followed by sequestration of Factor H to the cell surface and inhibition of complement-mediated cell lysis.
 ...
PMID:Factor H binding to bone sialoprotein and osteopontin enables tumor cell evasion of complement-mediated attack. 1074 89

The hormone 1alpha,25(OH)(2)-vitamin D(3) (125D) binds to its nuclear receptor (VDR) to stimulate gene transcription activity. Inversion of configuration at C-20 of the side chain to generate 20-epi-1alpha,25(OH)(2)D(3) (20E-125D) increases transcription 200-5000-fold over 125D with its 20-normal (20N) side chain. This enhancement has been attributed to the VDR ligand-binding domain (LBD) having different contact sites for 20N and 20E side chains that generate different VDR conformations. We synthesized 1alpha, 25-dihydroxy-21-(3-hydroxy-3-methylbutyl)vitamin D(3) (Gemini) with two six-carbon side chains (both 20N and 20E orientations). Energy minimization calculations indicate the Gemini side chain possesses significantly more energy minima than either 125D or 20E-125D (2346, 207, and 127 minima, respectively). We compared activities of 125D, 20E-125D, and Gemini, respectively, in several assays: binding to wild-type (100%, 147%, and 38%) and C-terminal-truncated mutant VDR; transcriptional activity (of the transfected osteopontin promoter in ROS 17/2.8 cells: ED(50) 10, 0.005, and 1.0 nM); mediation of conformational changes in VDR assessed by protease clipping (major trypsin-resistant fragment of 34, 34, and 28 kDa). For inhibition of cellular clonal growth of human leukemia (HL-60) and breast cancer (MCF7) cell lines, the ED(50)(125D)/ED(50)(Gem) was respectively 380 and 316. We conclude that while Gemini readily binds to the VDR and generates unique conformational changes, none of them is able to permit a superior gene transcription activity despite the presence of a 20E side chain.
 ...
PMID:Characterization of a novel analogue of 1alpha,25(OH)(2)-vitamin D(3) with two side chains: interaction with its nuclear receptor and cellular actions. 1089 9

The urokinase plasminogen activator (uPA) system has been widely associated with the development of breast carcinoma. However, the role of the urokinase pathway in the development of osseous breast cancer metastases has been largely overlooked. We studied the expression of uPA, urokinase plasminogen activator receptor (uPAR)- and plasminogen activator inhibitor type-1 (PAI-1) in human breast carcinomas and their bone metastases, using in situ hybridisation. Studies were performed using paraffin-embedded tissue from 13 ductal carcinomas, 23 invasive ductal carcinomas, five normal breasts and 25 bone metastases. The majority of the tumours examined expressed low to moderate levels of uPA mRNA and low to high levels of uPAR and PAI-1 mRNA, which was predominantly localised to the epithelial tumour cells. There was slight over-expression of uPA and PAI-1 mRNA and a marked increase in uPAR mRNA expression in the malignant tumours compared with benign tissue. Overall, uPAR and PAI-1 mRNA expression was found to be more variable than uPA mRNA, suggesting a possible role of the receptor and inhibitor in the regulation of uPA activity. Increased alpha1(I) procollagen (COL) and osteopontin (OPN) mRNA expression was detected, primarily in the stromal cells, in malignant tumours compared with the benign tissue. The increased expression of the components of the uPA system on the epithelial tumour cells may account for the activation of the proteolytic cascade that occurs during breast cancer metastasis to bone. Furthermore, the over-expression of COL and OPN suggests a possible interaction between these matrix proteins and the uPA system.
Breast Cancer Res Treat 2000 May
PMID:Urokinase plasminogen activator system gene expression is increased in human breast carcinoma and its bone metastases--a comparison of normal breast tissue, non-invasive and invasive carcinoma and osseous metastases. 1093 85

Overexpression of protein kinase C-alpha in MCF-7 breast cancer cells (MCF-7-PKC-alpha cells) results in anchorage-independent growth and increased tumorigenicity of these cells in nude mice. MCF-7-PKC-alpha cells, unlike their parental MCF-7 cells, are sensitized to apoptosis by phorbol esters. When adhered to osteopontin, a bone matrix protein, MCF-7-PKC-alpha cells were resistant to phorbol ester mediated apoptosis. Fluorescence-activated cell sorting revealed that osteopontin receptors, alphavbeta3 and alphavbeta5, are expressed on MCF-7-PKC-alpha cells and that both are used to adhere to osteopontin. Addition of an RGD-containing peptide inhibited survival of MCF-7-PKC-alpha cells exposed to phorbol ester and adhered to osteopontin. This indicated that an integrin was involved in the cell death suppression signal. Whereas, anti-alphavbeta5 antibody did not reduce survival of MCF-7-PKC-alpha cells adhered to osteopontin, anti-alphavbeta3 antibody could efficiently block suppression of apoptosis. Phorbol ester also induced increased expression of alphavbeta3 on MCF-7-PKC-alpha cells by upregulating expression of a second species of beta3 mRNA. This study suggests that breast cancer cells that have metastasized to bone may have a survival advantage resulting from interaction of alphavbeta3 on these cells with the bone protein osteopontin.
 ...
PMID:Adherence to osteopontin via alphavbeta3 suppresses phorbol ester-mediated apoptosis in MCF-7 breast cancer cells that overexpress protein kinase C-alpha. 1107 11


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>