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

Several years after the isolation of deleted in liver cancer 1 (DLC-1), a gene that encodes a Rho GTPase activating protein, the closely related DLC-2 gene was identified. DLC-1 and DLC-2 are approximately 50% identical and share the same SAM-RhoGAP-START domain organization. Since DLC-1 and -2 are located at chromosome regions that are commonly deleted in cancer cells and have been found to function as tumor suppressor genes, we sought to compare their expression profiles in several common types of cancer and to determine whether dlc1 and dlc2 proteins cooperate in tumor development. Using cancer-profiling arrays, we detected for the first time down-regulation of DLC-1 expression in renal, uterine and rectal cancers and down-regulation of DLC-2 expression in lung, ovarian, renal, breast, uterine, gastric, colon and rectal tumors. Since DLC-1 also functions as a metastasis suppressor gene in breast cancer, DLC-1 and DLC-2 expression were examined in a series of primary ductal carcinomas derived from patients with regional lymph node metastases. Using quantitative RT-PCR we detected a significantly lower expression of DLC-1 and DLC-2 in high percentage of tumors, suggesting that deficiency of either DLC gene facilitates dissemination of breast carcinoma cells to secondary sites. We examined DLC-2 expression in DLC-1-negative cell lines derived from human breast, non-small cell lung, and hepatocellular carcinomas, that could be rendered less or non-tumorigenic by ectopic expression of DLC-1. DLC-2 transcripts were detected in all cell lines, indicating that none of the cells were deficient in both members of the DLC family. This comparative expression analysis of DLC-1 and -2 identifies down-regulation of the two emerging bona fide tumor suppressor genes in additional types of solid tumors. The large spectrum of cancers with dysregulated DLC genes underlines the involvement of this family of genes in cancer development.
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PMID:Expression profile of the tumor suppressor genes DLC-1 and DLC-2 in solid tumors. 1701 43

The insulin receptor substrate (IRS) proteins are cytoplasmic adaptors that organize signaling complexes downstream of activated cell surface receptors. Here, we show that IRS-1 and IRS-2, despite significant homology, play critical yet distinct functions in breast cancer, and we identify specific signaling pathways that are influenced by IRS-1 using the polyoma virus middle-T (PyV-MT) transgenic mouse model of mammary carcinoma and Irs-1 null (Irs1(-/-)) mice. The absence of Irs-1 expression enhanced metastatic spread significantly without a significant effect on primary tumor growth. Orthotopic transplant studies revealed that the increased metastatic potential of Irs1-deficient tumor cells is cell autonomous. Mammary tumors that developed in PyV-MT::Irs1(-/-) mice exhibited elevated Irs-2 function and enhanced phosphatidylinositol 3-kinase/Akt/mTor activity, suggesting that one mechanism by which Irs-1 impedes metastasis is to suppress Irs-2-dependent signaling. In support of this mechanism, reduction of Irs-2 expression in Irs1(-/-) tumor cells restored mTor signaling to wild-type levels. PyV-MT::Irs1(-/-) tumors also exhibited a significant increase in vascular endothelial growth factor expression and microvessel density, which could facilitate their dissemination. The significance of our findings for human breast cancer is heightened by our observation that Irs-1 is inactivated in wild-type, metastatic mammary tumors by serine phosphorylation. Collectively, our findings reveal that inactivation of IRS-1 enhances breast cancer metastasis and support the novel hypothesis that IRS-1 has metastasis suppressor functions for breast cancer.
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PMID:Suppression of insulin receptor substrate 1 (IRS-1) promotes mammary tumor metastasis. 1703 Jun 5

Metastasis is the most frequent cause of death in patients with breast cancer. Tip30/CC3 gene is a putative metastasis suppressor gene, which was first identified by a differential display analysis of messenger RNA from the highly metastatic human variant small cell lung carcinoma (SCLC) versus less metastatic classic SCLC cell lines. The aim of this study was to analyze the relationship between expression of TIP30/CC3 and clinical prognosis in 87 patients with surgically removed breast carcinoma. Tumor tissues were stained immunohistochemically with anti-TIP30/CC3 antibody. We demonstrated that the expression of TIP30/CC3 was inversely associated with axillary lymph node metastasis (P = .0008) and vascular invasion (P = .0016). Expression of TIP30/CC3 was not correlated with tumor grade, estrogen, progesterone, and P53 expression. Inhibition of TIP30/CC3 expression by RNA-mediated interference greatly enhanced breast cancer cell invasion through the extracellular matrix, whereas overexpression of TIP30/CC3 by adenovirus vector suppressed invasion through the extracellular matrix. These data supported the theory that the expression of TIP30/CC3 had a suppressive function on tumor metastasis. In summary, the decrease in expression of TIP30/CC3 is related to metastasis and may represent a new prognosticator in breast carcinoma.
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PMID:TIP30/CC3 expression in breast carcinoma: relation to metastasis, clinicopathologic parameters, and P53 expression. 1709 32

BRMS1 is regarded as a metastasis suppressor gene for its ability to reduce metastatic potential of human and murine breast cancer cells as well as human melanoma cells. However, BRMS1 association to human tumor progression is not clearly understood. In the present study we analyzed BRMS1 mRNA expression in tumor progression and its potential prognostic value for breast carcinoma. BRMS1 mRNA expression level was quantified by real-time PCR in 47 tumoral, in 14 peritumoral and in 15 metastatic microdissected cellular populations from 47 breast cancer patients with 10-year follow up. We found BRMS1 expression to be higher in carcinoma cells than in matching normal epithelial cell populations in 10 out of 14 cases (p = 0.0005), while lymph-nodal carcinoma cells showed lower BRMS1 expression in 9 out of 15 cases (p = 0.001). Using both in vivo (human mammary breast carcinomas) and in vitro systems (breast cancer cell lines) we were able to demonstrate that BRMS1 overexpression was not a bias effect induced by cell proliferation rate. BRMS1 expression levels did not correlate with standard breast cancer prognostic factors but BRMS1 higher expression was associated with patient shorter disease-free and overall survival. Our findings are apparently inconsistent with the concept of BRMS1 as a metastasis suppressor gene. One possible explanation is that epithelial cells increase their BRMS1 expression as a compensatory response to tumor formation or metastasis progression, which is elevated in proportion to tumor aggressiveness, whereas those cells of the primary tumor that cannot upregulate BRMS1 escape to form metastasis.
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PMID:High level of messenger RNA for BRMS1 in primary breast carcinomas is associated with poor prognosis. 1716 20

KiSS1 is a putative metastasis suppressor gene in melanoma and breast cancer-encoding kisspeptins, which are also described as neuroendocrine regulators of the gonadotropic axis. Negative as well as positive regulation of KiSS1 gene expression by estradiol (E(2)) has been reported in the hypothalamus. Estrogen receptor alpha (ERalpha level is recognized as a marker of breast cancer, raising the question of whether expression of KiSS1 and its G-protein-coupled receptor (GPR54) is down- or upregulated by estrogens in breast cancer cells. KiSS1 was found to be expressed in MDA-MB-231, MCF7, and T47D cell lines, but not in ZR75-1, L56Br, and MDA-MB-435 cells. KiSS1 mRNA levels decreased significantly in ERalpha-negative MDA-MB-231 cells expressing recombinant ERalpha. In contrast, tamoxifen (TAM) treatment of ERalpha-positive MCF7 and T47D cells increased KiSS1 and GPR54 levels. The clinical relevance of this negative regulation of KiSS1 and GPR54 by E(2) was then studied in postmenopausal breast cancers. KiSS1 mRNA increased with the grade of the breast tumors. ERalpha-positive invasive primary tumors expressed sevenfold lower KiSS1 levels than ERalpha-negative tumors. Among ERalpha-positive breast tumors from postmenopausal women treated with TAM, high KiSS1 combined with high GPR54 mRNA tumoral levels was unexpectedly associated with shorter relapse-free survival (RFS) relative to tumors expressing low tumoral mRNA levels of both genes. The contradictory observation of putative metastasis inhibitor role of kisspeptins and RFS to TAM treatment suggests that evaluation of KiSS1 and its receptor tumoral mRNA levels could be new interesting markers of the tumoral resistance to anti-estrogen treatment.
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PMID:High tumoral levels of Kiss1 and G-protein-coupled receptor 54 expression are correlated with poor prognosis of estrogen receptor-positive breast tumors. 1791 99

A search for general regulators of cancer metastasis has yielded a set of microRNAs for which expression is specifically lost as human breast cancer cells develop metastatic potential. Here we show that restoring the expression of these microRNAs in malignant cells suppresses lung and bone metastasis by human cancer cells in vivo. Of these microRNAs, miR-126 restoration reduces overall tumour growth and proliferation, whereas miR-335 inhibits metastatic cell invasion. miR-335 regulates a set of genes whose collective expression in a large cohort of human tumours is associated with risk of distal metastasis. miR-335 suppresses metastasis and migration through targeting of the progenitor cell transcription factor SOX4 and extracellular matrix component tenascin C. Expression of miR-126 and miR-335 is lost in the majority of primary breast tumours from patients who relapse, and the loss of expression of either microRNA is associated with poor distal metastasis-free survival. miR-335 and miR-126 are thus identified as metastasis suppressor microRNAs in human breast cancer.
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PMID:Endogenous human microRNAs that suppress breast cancer metastasis. 1818 80

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

We have investigated protein kinase C (PKC) signaling, a putative differentiation-related and metastasis suppressor gene Cap43/NDRG1/Drg-1, and Y-box binding protein-1 (YB-1) to identify new molecular targeting for breast cancer. PKC is a family of serine/threonine kinases that is involved in the regulation of cell growth. We have demonstrated that PKC caused G(1) arrest in a breast cancer cell line through a mechanism involving a PKC-ERK MAPK-JNK-Rb protein signaling pathway. We have also characterized a novel mechanism through which all-trans retinoic acid (ATRA) and antineoplaston, anticancer drug, caused cell growth inhibition in breast cancer cells through effects on intracellular pathways. ATRA decreased the expression of PKCalpha, as well as reduced ERK MAPK phosphorylation, and consequently caused G(1) arrest. Antineoplaston caused the down-regulation of PKCalpha protein expression, resulting in inhibition of ERK MAPK phosphorylation, with resultant inhibition of Rb phosphorylation leading to G(1) arrest. PKC signaling represents a promising target for development of novel therapeutic agents. Cap43 is known as N-myc downstream-regulated gene 1 (NDRG1). Treatment with estradiol (E(2)) significantly decreased the expression of Cap43 in ER-alpha-positive breast cancer cell lines. Co-administration of tamoxifen abrogated the E(2)-induced downregulation of Cap43 in ER-alpha-positive cell lines. These results suggested that Cap43 may hold the potential of being a molecular marker to determine the therapeutic efficacy of anti-estrogenic anticancer agents in breast cancer. YB-1 is a member of the cold shock domain protein family. The expression of nuclear YB-1 was correlated with HER2 positively in clinical specimens of human breast cancer. Immunostaining studies showed that nuclear YB-1 expression was an independent prognostic factor of overall survival. Expression of nuclear YB-1 played an essential role in acquirement of malignant characteristics through HER2-dependent pathways in breast cancer patients. PKC, Cap43 and YB-1 may be useful in new molecular-targeting diagnosis and therapeutics in breast cancer.
Breast Cancer 2008
PMID:Preclinical studies of molecular-targeting diagnostic and therapeutic strategies against breast cancer. 1822 98

IFIXalpha, a member of the interferon-inducible HIN-200 family, has been identified as a putative tumor suppressor. However, the molecular mechanisms underlying IFIXalpha-mediated tumor suppression are poorly understood. In the present study, we demonstrated that the metastasis suppressor maspin acts as the downstream target of IFIXalpha. IFIXalpha suppressed the invasion activity of MDA-MB-468 breast cancer cells, and its inhibitory effect was reversed by the knockdown of maspin. Both Maspin mRNA and protein were upregulated by IFIXalpha. Histone deacetylase (HDAC) inhibitors, but not DNA methyltransferase inhibitor upregulated maspin, and HDAC1 inhibited the transactivation of maspin promoter. Although the HDAC1 protein was downregulated in IFIXalpha-expressing cells, IFIXalpha did not affect HDAC1 mRNA levels. Conversely, a proteasome inhibitor restored the level of HDAC1 protein in IFIXalpha-expressing cells, and the polyubiqutination of HDAC1 was promoted by IFIXalpha, suggesting that HDAC1 is regulated by IFIXalpha through a ubiquitin-proteasome pathway. Together, these data provide novel insights into the tumor-suppressive function of IFIXalpha.
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PMID:Interferon-inducible protein IFIXalpha inhibits cell invasion by upregulating the metastasis suppressor maspin. 1824 78

Breast cancer cells exhibit complex karyotypic alterations causing deregulation of numerous genes. Some of these genes are probably causal for cancer formation and local growth whereas others are causal for the various steps of metastasis. In a fraction of tumors deregulation of the same genes might be caused by epigenetic modulations, point mutations or the influence of other genes. We have investigated the relation of gene expression and chromosomal position, using eight datasets including more than 1200 breast tumors, to identify chromosomal regions and candidate genes possibly causal for breast cancer metastasis. By use of "Gene Set Enrichment Analysis" we have ranked chromosomal regions according to their relation to metastasis. Overrepresentation analysis identified regions with increased expression for chromosome 1q41-42, 8q24, 12q14, 16q22, 16q24, 17q12-21.2, 17q21-23, 17q25, 20q11, and 20q13 among metastasizing tumors and reduced gene expression at 1p31-21, 8p22-21, and 14q24. By analysis of genes with extremely imbalanced expression in these regions we identified DIRAS3 at 1p31, PSD3, LPL, EPHX2 at 8p21-22, and FOS at 14q24 as candidate metastasis suppressor genes. Potential metastasis promoting genes includes RECQL4 at 8q24, PRMT7 at 16q22, GINS2 at 16q24, and AURKA at 20q13.
Breast Cancer Res Treat 2009 Jan
PMID:Gene expression meta-analysis identifies chromosomal regions and candidate genes involved in breast cancer metastasis. 1829 85


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