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

Breast calcification is an important feature in the radiological assessment of breast lesions. There are well established diagnostic criteria basing on the morphology and distribution of the calcifications radiologically with recommendation protocols. Pathologically, calcifications in breast lesions are of dystrophic type, and may occur in either the secretory materials or necrotic debris, with inflammation and osteopontin being plausible mediators. Detection of calcium phosphate (hydroyapaptite) is considerably easier than calcium oxalate. Radiologically amorphous calcification represents a borderline type of calcification, and occurs in both benign and malignant (low grade) lesions, and warrants careful follow up and investigation. Clustering of calcification alone may not be an accurate predictor for malignancy, but when there are associated features like pleomorphism, branching, architectural distortion, and associated mass or density, the predictive value for malignant increases. Adequate sampling of calcification in the biopsy is crucial in the management of patients; in general, needle core biopsy or mammotome biopsy achieve satisfactory calcification retrieval. In a benign biopsy that fails to identify the calcifications visible in the mammography, further evaluation or cutting of the histologic block is recommended to minimize the potential of a false negative investigation.
Breast Cancer Res Treat 2008 Jul
PMID:Intermediate to highly suspicious calcification in breast lesions: a radio-pathologic correlation. 1767 89

Despite their potential to impact diagnosis and treatment of cancer, few protein biomarkers are in clinical use. Biomarker discovery is plagued with difficulties ranging from technological (inability to globally interrogate proteomes) to biological (genetic and environmental differences among patients and their tumors). We urgently need paradigms for biomarker discovery. To minimize biological variation and facilitate testing of proteomic approaches, we employed a mouse model of breast cancer. Specifically, we performed LC-MS/MS of tumor and normal mammary tissue from a conditional HER2/Neu-driven mouse model of breast cancer, identifying 6758 peptides representing >700 proteins. We developed a novel statistical approach (SASPECT) for prioritizing proteins differentially represented in LC-MS/MS datasets and identified proteins over- or under-represented in tumors. Using a combination of antibody-based approaches and multiple reaction monitoring-mass spectrometry (MRM-MS), we confirmed the overproduction of multiple proteins at the tissue level, identified fibulin-2 as a plasma biomarker, and extensively characterized osteopontin as a plasma biomarker capable of early disease detection in the mouse. Our results show that a staged pipeline employing shotgun-based comparative proteomics for biomarker discovery and multiple reaction monitoring for confirmation of biomarker candidates is capable of finding novel tissue and plasma biomarkers in a mouse model of breast cancer. Furthermore, the approach can be extended to find biomarkers relevant to human disease.
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PMID:Integrated pipeline for mass spectrometry-based discovery and confirmation of biomarkers demonstrated in a mouse model of breast cancer. 1799 39

Osteopontin (OPN) is a secreted protein that is overexpressed in a number of human cancers, and has been associated with increased metastatic burden and poor prognosis in breast cancer patients. The OPN protein contains several conserved structural elements including heparin- and calcium-binding domains, a thrombin-cleavage site, a CD44 binding site, and two integrin-binding sites. Experimental studies have shown that the ability of OPN to interact with a diverse range of factors, including cell surface receptors (integrins, CD44), secreted proteases (matrix metalloproteinases, urokinase plasminogen activator), and growth factor/receptor pathways (TGFalpha/EGFR, HGF/Met) is central to its role in malignancy. These complex signaling interactions can result in changes in gene expression, which ultimately lead to alterations in cell properties involved in malignancy such as adhesion, migration, invasion, enhanced tumor cell survival, tumor angiogenesis, and metastasis. Therefore, OPN is not merely associated with cancer, but rather it plays a multi-faceted functional role via complex molecular cross-talk with other factors. This review will focus on the role of OPN in breast cancer, in particular on the malignancy-promoting aspects of OPN that may reveal opportunities for new approaches to the clinical management of breast cancer.
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PMID:Osteopontin overexpression in breast cancer: knowledge gained and possible implications for clinical management. 1772 86

While the acquisition of invasiveness is a critical step in early stage breast carcinomas (DCIS), no established molecular markers reliably identify tumor progression. The metastasis gene osteopontin is subject to alternative splicing, which yields 3 messages, osteopontin-a, osteopontin-b and osteopontin-c. Osteopontin-c is selectively expressed in invasive, but not in noninvasive, breast tumor cell lines, and it effectively supports anchorage independence. We evaluated osteopontin-c as a biomarker. The RNA message for osteopontin-c was present in 16 of 20 breast cancers (80%), but was undetectable in 22 normal specimens obtained from reduction mammoplasty. In contrast, osteopontin-a RNA was expressed at various levels in all 20 breast cancers, 11 tumor-surrounding tissues and 21 normal samples. The splice variant osteopontin-b was present at barely detectable levels in 18 of 20 cancers and in 6 of 22 normal breasts. By immunohistochemistry, 66 of 69 normal breasts were negative, while 3 showed low level staining. Among the breast cancers, 43 of 56 cores (77%) stained positive for osteopontin-c. When correlated with tumor grade, the staining for osteopontin-c increased from grade 1 to grade 3. In a total of 178 breast specimens analyzed, osteopontin-c was present in 78% of cancers, 36% of surrounding tissues and 0% of normal tissues. Furthermore, osteopontin-c detects a higher fraction of breast cancers than estrogen receptor (ER), progesterone receptor or HER2. In conjunction, osteopontin-c, ER and HER2 reliably predict grade 2-3 breast cancer. Hence, osteopontin-c is a diagnostic and prognostic marker that may have value in a diagnostic panel together with conventional breast cancer markers.
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PMID:Osteopontin-c is a selective marker of breast cancer. 1830 53

Osteopontin (OPN) has been clinically and experimentally associated with breast cancer metastasis. Proteolytic cleavage of OPN by thrombin has been reported to increase its biologic activity. The purpose of this study was to determine if inhibition of thrombin could reduce the malignancy-promoting effects of OPN on breast cancer cell behavior in vitro and in vivo. MDA-MB-468 human breast cancer cells were stably transfected to overexpress OPN (468-OPN) or a control vector (468-CON) and compared for functional differences in malignant/metastatic behavior in response to treatment with the thrombin-specific inhibitor Argatroban. Western blot analysis revealed that both 468-CON and 468-OPN cells produce thrombin and the thrombin-related protein tissue factor, and express very low levels of thrombin receptor (PAR-1). In vitro assays demonstrated that Argatroban treatment (25 microg/ml) of 468-OPN cells resulted in decreased cell growth, colony-forming ability, adhesion, and migration relative to untreated controls (P < 0.05), but did not have a significant effect on 468-CON cells. Following mammary fat pad injection, treatment with Argatroban (9 mg/kg/day) increased the in vivo tumor latency of both 468-CON and 468-OPN cells, and reduced primary tumor growth of 468-OPN cells (relative to untreated controls; P < 0.05). Furthermore, Argatroban treatment significantly decreased lymphatic metastasis of both 468-CON (P < 0.04) and 468-OPN (P < 0.01) cells relative to untreated controls. These novel findings indicate that inhibition of thrombin can reduce malignant and metastatic behavior of MDA-MB-468 breast cancer cells using both OPN-dependent and OPN-independent mechanisms, and suggest that thrombin inhibitors such as Argatroban may hold potential as therapeutic agents to combat breast cancer progression.
Breast Cancer Res Treat 2008 Nov
PMID:The thrombin inhibitor Argatroban reduces breast cancer malignancy and metastasis via osteopontin-dependent and osteopontin-independent mechanisms. 1809 47

Angiogenesis is the hallmark of cancer, and development of aggressiveness of primary tumor depends on de novo angiogenesis. Here, using multiple in vitro and in vivo models, we report that osteopontin (OPN) triggers vascular endothelial growth factor (VEGF)-dependent tumor progression and angiogenesis by activating breast tumor kinase (Brk)/nuclear factor-inducing kinase/nuclear factor-kappaB (NF-kappaB)/activating transcription factor-4 (ATF-4) signaling cascades through autocrine and paracrine mechanisms in breast cancer system. Our results revealed that both exogenous and tumor-derived OPN play significant roles in VEGF-dependent tumor angiogenesis. Clinical specimen analysis showed that OPN and VEGF expressions correlate with levels of neuropilin-1, Brk, NF-kappaB, and ATF-4 in different grades of breast cancer. Consequently, OPN plays essential role in two key aspects of tumor progression: VEGF expression by tumor cells and VEGF-stimulated neovascularization. Thus, targeting OPN and its regulated signaling network could be a novel strategy to block tumor angiogenesis and may develop an effective therapeutic approach for the management of breast cancer.
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PMID:Osteopontin promotes vascular endothelial growth factor-dependent breast tumor growth and angiogenesis via autocrine and paracrine mechanisms. 2716 Mar 11

The BRMS1 metastasis suppressor interacts with the protein AT-rich interactive domain 4A (ARID4A, RBBP1) as part of SIN3.histone deacetylase chromatin remodeling complexes. These transcriptional co-repressors regulate diverse cell phenotypes depending upon complex composition. To define BRMS1 complexes and their roles in metastasis suppression, we generated BRMS1 mutants (BRMS1(mut)) and mapped ARID4A interactions. BRMS1(L174D) disrupted direct interaction with ARID4A in yeast two-hybrid genetic screens but retained an indirect association with ARID4A in MDA-MB-231 and -435 human breast cancer cell lines by co-immunoprecipitation. Deletion of the first coiled-coil domain (BRMS1(DeltaCC1)) did not disrupt direct interaction in yeast two-hybrid screens but did prevent association by co-immunoprecipitation. These results suggest altered complex composition with BRMS1(mut). Although basal transcription repression was impaired and the pro-metastatic protein osteopontin was differentially down-regulated by BRMS1(L174D) and BRMS1(DeltaCC1), both down-regulated the epidermal growth factor receptor and suppressed metastasis in MDA-MB-231 and -435 breast cancer xenograft models. We conclude that BRMS1(mut), which modifies the composition of a SIN3.histone deacetylase chromatin remodeling complex, leads to altered gene expression profiles. Because metastasis requires the coordinate expression of multiple genes, down-regulation of at least one important gene, such as the epidermal growth factor receptor, had the ability to suppress metastasis. Understanding which interactions are necessary for particular biochemical/cellular functions may prove important for future strategies targeting metastasis.
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PMID:Alterations of BRMS1-ARID4A interaction modify gene expression but still suppress metastasis in human breast cancer cells. 1821

Development of breast tumour malignancies results in enhanced expression of various oncogenic molecules. Elevated expression of osteopontin (OPN) in higher grades of breast carcinoma correlates with enhanced expressions of several oncogenic molecules (urokinase-type plasminogen activator [uPA], matrix metalloproteinase-2/-9 [MMP-2 and -9]) and increased angiogenic potential of breast carcinoma. In this study, using in vitro and multiple in vivo models, we have demonstrated that silencing of OPN by its specific small interfering RNA (siRNA) down-regulates the expressions of oncogenic molecules such as uPA, MMP-2 and -9 resulting in inhibition of in vitro cell motility and in vivo tumourigenicity in mice. Moreover our results demonstrated that OPN-/- mice showed slower progression of tumour growth in breast cancer model as compared to wild-type mice. Furthermore, the data showed that injection of carcinogenic compound, pristane (2, 6,10,14-tetramethylpen-tadecane) induces breast tumour progression leading to enhanced expression of OPN and other oncogenic molecules in mammary fat pad of nude- and wild-type mice but not in OPN-/- mice. However, intratumoural injection of OPN siRNA to pristane-induced tumour significantly suppressed these effects. Our data revealed that knocking down of OPN effectively curb breast cancer progression and further suggested that developing of OPN-based therapeutics might be an emerging approach for the next generation of breast cancer management.
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PMID:Down-regulation of osteopontin attenuates breast tumour progression in vivo. 1841 94

The T cell factor 4 (Tcf-4) interacts with beta-catenin in the Wnt signalling pathway and coactivates downstream target genes in diverse systems including the breast. This activity is important during normal development but its deregulation plays a pivotal role in cancer progression. In a rat model for breast cancer it has been shown that metastasis-inducing DNA (Met-DNA) sequesters the endogenous inhibitory Tcf-4 and thereby promotes transcription of the secreted extracellular matrix glycophosphoprotein, osteopontin, the direct effector of metastasis in this model system. Permanent transfection of the benign rat mammary cell line with a fragment from the Met-DNA containing the Tcf recognition sequence CAAAG induces the cells to metastasize in syngeneic rats in vivo. Tcf-4 expression in human breast carcinomas is inversely associated with osteopontin protein levels. High Tcf-4 expression impedes both OPN promoter activity and protein expression in rat mammary carcinoma cells. Understanding the role of Tcf-4 in cancer development and its transcription regulation should lay the foundation for novel therapeutic approaches in the future.
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PMID:The role of LEF/TCF factors in neoplastic transformation. 1828 12

Effective inhibitors of osteopontin (OPN)-mediated neoplastic transformation and metastasis are still lacking. (-)-Agelastatin A is a naturally occurring oroidin alkaloid with powerful antitumor effects that, in many cases, are superior to cisplatin in vitro. In this regard, past comparative assaying of the two agents against a range of human tumor cell lines has revealed that typically (-)-agelastatin A is 1.5 to 16 times more potent than cisplatin at inhibiting cell growth, its effects being most pronounced against human bladder, skin, colon, and breast carcinomas. In this study, we have investigated the effects of (-)-agelastatin A on OPN-mediated malignant transformation using mammary epithelial cell lines. Treatment with (-)-agelastatin A inhibited OPN protein expression and enhanced expression of the cellular OPN inhibitor, Tcf-4. (-)-Agelastatin A treatment also reduced beta-catenin protein expression and reduced anchorage-independent growth, adhesion, and invasion in R37 OPN pBK-CMV and C9 cell lines. Similar effects were observed in MDA-MB-231 and MDA-MB-435s human breast cancer cell lines exposed to (-)-agelastatin A. Suppression of Tcf-4 by RNA interference (short interfering RNA) induced malignant/invasive transformation in parental benign Rama 37 cells; significantly, these events were reversed by treatment with (-)-agelastatin A. Our study reveals, for the very first time, that (-)-agelastatin A down-regulates beta-catenin expression while simultaneously up-regulating Tcf-4 and that these combined effects cause repression of OPN and inhibition of OPN-mediated malignant cell invasion, adhesion, and colony formation in vitro. We have also shown that (-)-agelastatin A inhibits cancer cell proliferation by causing cells to accumulate in the G(2) phase of cell cycle.
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PMID:Agelastatin A: a novel inhibitor of osteopontin-mediated adhesion, invasion, and colony formation. 1834 42


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