UMLS:C0006142 - FACTA Search

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

Human SNAIL1 (SNAI1) protein encoded by SNAI1/SNA gene represses transcription of E-cadherin/CDH1 gene. Human SNAIL2 (SNAI2) protein encoded by SNAI2/SLUG gene induces the first phase of epithelial-mesenchymal transition (EMT), including desmosome dissociation, cell spreading, and initiation of cell separation. Here, we have identified human SNAIL3 (SNAI3) gene using bioinformatics. Human SNAI3 gene, consisting of at least three exons, spans around the nucleotide position 320214-328221 of human reference genomic contig NT_010404.8 in the reverse orientation. SNAI3 gene, was located between KIAA0233 gene and CBFA2T3 gene in human chromosome 16q24.3, a region affected in breast cancer, gastric cancer, hepatocellular carcinoma, ovarian cancer, and therapy-related myeloid leukemia with t(16;21)(q24;q22) translocation. Human SNAI3 gene was found to encode 292-amino-acid polypeptide with the N-terminal SNAG domain and five zinc finger domains. N-terminal SNAG domain was identified in zinc finger proteins SNAI1, SNAI2, SNAI3, SCRATCH (SCRT1), GFI1, and GFI1B. ATP/GTP binding site was identified in SCRT1, GFI1 and GFI1B, but not in SNAI1, SNAI2 and SNAI3. Phylogenetic analysis of human zinc finger proteins with SNAG domain revealed that SNAI1, SNAI2 and SNAI3 were more closely related. These results clearly indicate that SNAI1, SNAI2 and SNAI3 constitute a subfamily among SNAG zinc-finger proteins. Human SNAI3 mRNA was expressed in skin melanotic melanoma, lung epidermoid carcinoma, and germ cell tumor. Because SNAG zinc-finger proteins are transcriptional repressors implicated in carcinogenesis and embryogenesis, SNAI3 gene might be a potent target of pharmacogenomics in the field of oncology and regenerative medicine.
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PMID:Identification and characterization of human SNAIL3 (SNAI3) gene in silico. 1257 45

SEMA3F, isolated from a 3p21.3 deletion, has antitumor activity in transfected cells, and protein expression correlates with tumor stage and histology. In primary tumors, SEMA3F and VEGF surface staining is inversely correlated. Coupled with SEMA3F at the leading edge of motile cells, we previously suggested that both proteins competitively regulate cell motility and adhesion. We have investigated this using the breast cancer cell line, MCF7. SEMA3F inhibited cell attachment and spreading as evidenced by loss of lamellipodia extensions, membrane ruffling, and cell-cell contacts, with cells eventually rounding-up and detaching. In contrast, VEGF had opposite effects. Although SEMA3F binds NRP2 with 10-fold greater affinity than NRP1, the effects in MCF7 were mediated by NRP1. This was determined by receptor expression and blocking of anti-NRP1 antibodies. Similar effects, but through NRP2, were observed in the C100 breast cancer cell line. Although we were unable to demonstrate changes in total GTP-bound Rac1 or RhoA, we did observe changes in the localization of Rac1-GFP using time lapse microscopy. Following SEMA3F, Rac1 moved to the base of lamellipodia and - with their collapse - to the membrane. These results support the concept that SEMA3F and VEGF have antagonistic actions affecting motility in primary tumor cell.
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PMID:Semaphorin SEMA3F and VEGF have opposing effects on cell attachment and spreading. 1265 73

Tamoxifen (TAM) provides an effective agent for treatment of hormone-dependent breast cancer but resistance uniformly ensues upon continued use. Additional studies are required to define more precisely the mechanisms involved in development of resistance. We conducted systematic experimental and clinical studies based on the hypothesis that tumors exposed to TAM long-term may develop resistance by becoming hypersensitive to its estrogenic effects. These investigations uncovered new features of the TAM resistance (TR) phenomenon and identified possible means for its prevention and/or elimination. Initially we confirmed that TR may be divided into two subtypes, primary and acquired resistance, and that these differ by certain important characteristics including the level of the possible involvement of adaptive and genetic components. Then we distinguished at least three consequent stages of this phenomenon: stage I when TAM behaves as an antiestrogen, stage II with development of increased sensitivity to the agonistic (pro-estrogenic) properties of TAM and stage III with an adaptive increase in sensitivity to estradiol (E(2)). During this evolutionary process, as shown in vitro, MAP kinase (MAPK) and aromatase activities increase. The time frame of the increase in MAPK activity as a rule outpaces the increase in aromatase activity during the course of the development of TR. This may occur as a response to estrogen deprivation or interruption of the process of estrogen signaling and can be one of the promoting factors of increased aromatase activation. On the other hand, the chronology of these events indicates that changes in the MAPK cascade can be more important for the early steps of the development and maintenance of the TR state. Changes in local estrogen production/sensitivity to E(2) are perhaps essential for the later steps of this phenomenon. We have explored the use of a growth factor-blocking agent to abrogate the adaptive changes in sensitivity. Farnesylthiosalicylic acid (FTS), an inhibitor of GTP-Ras binding to its membrane acceptor site, reduces the increase in the number of MCF-7 cells induced by long-term TAM treatment. It also decreases MAPK activity in TAM-treated MCF-7 cells and in established TR cell lines. Alone or in combination with letrozole (presumably, through the influence on MAPK pathway) FTS exerts moderate inhibitory effects on aromatase activity in estrogen-deprived or estrogen-exposed MCF-7 cells. Taken together, our observations suggest that FTS is a 'candidate drug' for the treatment of TR. Both the adaptive and genetic types of resistance may be amenable to this approach. Our studies underline the possible importance of starting the treatment/prevention of TR early on. From our clinical studies using immunohistochemistry, there is a rather strong rationale to include as a predisposing factor in the development of TR the increase in MAPK and aromatase activities in human primary breast tumors. In summary, data obtained during the course of this project may be considered as evidence supporting the principle that processes resulting in responses to TAM as an agonist and the development of estrogen hypersensitivity of breast cancer cells could potentially be mechanistically linked.
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PMID:New approaches to the understanding of tamoxifen action and resistance. 1279 Jul 88

A variety of phenotypic characteristics are required for a cancer cell to successfully complete the metastatic cascade. Acquisition of a motile and invasive phenotype is one requirement for a cell to become metastatically competent. The Rho (Ras homology) GTPases are a subfamily of small GTP-binding proteins, which are related to the Ras oncogene. All aspects of cellular motility and invasion are controlled by the Rho GTPases and are closely linked to signals from the extracellular environment, particularly in response to growth factors. Dysregulation of Rho activation through aberrant growth-factor signaling, loss of function of key Rho-regulatory proteins or overexpression of Rho mRNA could result in increased Rho activity and cellular motility. Therefore, the importance of the Rho GTPases in the progression of aggressive cancers, is becoming more appreciated.
Breast Cancer Res 2003
PMID:Inflammatory breast cancer: relationship between growth factor signaling and motility in aggressive cancers. 1279 1

The Rho family GTPases RhoA, RhoB, and RhoC regulate the actin cytoskeleton, cell movement, and cell growth. Unlike Ras, up-regulation or overexpression of these GDP/GTP binding molecular switches, but not activating point mutations, has been associated with human cancer. Although they share over 85% sequence identity, RhoA, RhoB, and RhoC appear to play distinct roles in cell transformation and metastasis. In NIH 3T3 cells, RhoA or RhoB overexpression causes transformation whereas RhoC increases the cell migration rate. To specifically target RhoA, RhoB, or RhoC function, we have generated a set of chimeric molecules by fusing the RhoGAP domain of p190, a GTPase-activating protein that accelerates the intrinsic GTPase activity of all three Rho GTPases, with the C-terminal hypervariable sequences of RhoA, RhoB, or RhoC. The p190-Rho chimeras were active as GTPase-activating proteins toward RhoA in vitro, co-localized with the respective active Rho proteins, and specifically down-regulated Rho protein activities in cells depending on which Rho GTPase sequences were included in the chimeras. In particular, the p190-RhoA-C chimera specifically inhibited RhoA-induced transformation whereas p190-RhoC-C specifically reversed the migration phenotype induced by the active RhoC. In human mammary epithelial-RhoC breast cancer cells, p190-RhoC-C, but not p190-RhoA-C or p190-RhoB-C, reversed the anchorage-independent growth and invasion phenotypes caused by RhoC overexpression. In the highly metastatic A375-M human melanoma cells, p190-RhoC-C specifically reversed migration, and invasion phenotypes attributed to RhoC up-regulation. Thus, we have developed a novel strategy utilizing RhoGAP-Rho chimeras to specifically down-regulate individual Rho activity and demonstrate that this approach may be applied to multiple human tumor cells to reverse the growth and/or invasion phenotypes associated with disregulation of a distinct subtype of Rho GTPase.
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PMID:A novel strategy for specifically down-regulating individual Rho GTPase activity in tumor cells. 1293 57

While advances in molecular genetics have provided new insights into molecular alterations that lead to the development of many tumors, including breast carcinoma, the genetic and epigenetic alterations that result in metastatic spread of the disease, from which afflicted patients ultimately succumb, are much more poorly understood. Important biologic processes in the development of metastasis include increased migration and invasion of tumor cells. While the regulation of these processes is complex, they are controlled in part by small G proteins of the Rho family, including Rho, Rac, and Cdc42, that are involved in cytoskeletal organization. These proteins, active when bound to GTP, are, in turn, regulated by guanine nucleotide exchange factors (GNEFs) and guanine nucleotide activating proteins. The GNEF Tiam1 catalyzes nucleotide exchange for Rac in vivo, and Rac, Cdc42 and Rho in vitro. Tiam1 was identified first in 1994 by in vitro selection for invasiveness in T-lymphoma cells. Accordingly, Tiam1 has been shown to increase invasion in T-lymphoma cells, as well as to increase cellular migration in fibroblasts, and to promote motility in some neuronal cells. In contrast, Tiam1 has been demonstrated to increase cellular adhesion in some epithelial cell populations. Thus, Tiam1 has multiple roles in regulating cellular functions, likely dependent on the cell type, the substratum, transformation status of the cells, and the activation state of small G proteins in a given cell. Increasing evidence has focused on Tiam1's regulation, as well as Tiam1's role in cancer progression and metastasis. Recent results from other laboratories and ours have demonstrated that increased Tiam1 expression correlates with grade of breast cancer in humans and metastatic potential of human breast carcinoma cell lines in nude mice. This review will discuss Tiam1's cellular functions and methods of regulation, and will highlight Tiam1's contribution to cancer progression and metastasis.
Breast Cancer Res Treat 2004 Mar
PMID:The role of the guanine nucleotide exchange factor Tiam1 in cellular migration, invasion, adhesion and tumor progression. 1499 51

In most human breast cancer cell lines, there is a direct correlation between their in vivo invasive phenotypes and in vitro invasion activities. Here, we found that ADP-ribosylation factor 6 (Arf6) is localized at the invadopodia of the cultured breast cancer cells MDA-MB-231, and its suppression by a small-interfering RNA duplex effectively blocks the invasive activities of the cells, such as invadopodia formation, localized matrix degradation and Matrigel transmigration but not the cell-adhesion activity. We also found that the GTP hydrolysis-defective mutant Arf6(Q67L) and the GTP-binding defective mutant Arf6(T27N) both blocked these invasive activities but not cell adhesion, suggesting the necessity of continued activation and cycling of the Arf6 GTPase cycle in invasion. Among the different human breast cancer cell lines that we examined, cell lines with high invasive activities expressed higher amounts of Arf6 protein than those in weakly invasive and noninvasive cell lines, although no notable correlation was found between Arf6 mRNA expression levels and invasive activities. Moreover, Matrigel-transmigration activity of all of these invasive cells was blocked effectively by an Arf6 small-interfering RNA duplex. Hence, Arf6 appears to be an integral component of breast cancer invasive activities, and we propose that Arf6 and the intracellular machinery regulating Arf6 during invasion should be considered as therapeutic targets for the prevention of breast cancer invasion.
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PMID:Requirement for Arf6 in breast cancer invasive activities. 1508 4

The RHO family of small GTPases has multiple functions, including regulation of cytoskeletal organization, cell cycle progression and cell migration, among others. The key members of this family are RHO, RAC and CDC42. Active GTP-bound RHO proteins are down-regulated by RHO GTPase-activating proteins (RHOGAPs). Herein, we describe the identification, characterization and mutational analysis of a novel RHOGAP designated as ARHGAP8, which is located within a critical region of loss-of-heterozygosity on chromosome 22q13.31 in breast and colorectal carcinomas. ARHGAP8 shares an identical genomic organization with ARHGAP1/CDC42GAP/p50RHOGAP and the corresponding proteins share the same functional domains that distinguish them from other ARHGAP members. These domains include the C-terminal RHOGAP domain, a central SH3-binding motif, and an N-terminal BNIP-2/CDC42GAP homology (BCH)/Sec14p-like domain. Three alternatively spliced ARHGAP8 transcripts were expressed in normal mammary gland and colon, which differed in the size of the BCH/Sec14p-like domain only. PCR-SSCP analyses revealed a total of six germline missense variants in individuals with colorectal or breast cancer; however, somatic mutations were not identified. Surprisingly, ARHGAP8 expression was up-regulated in the majority of primary colorectal tumors analyzed. Taken together, ARHGAP8 encodes a novel RHOGAP with unique functional domains that is highly homologous to ARHGAP1/CDC42GAP/p50RHOGAP.
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PMID:ARHGAP8 is a novel member of the RHOGAP family related to ARHGAP1/CDC42GAP/p50RHOGAP: mutation and expression analyses in colorectal and breast cancers. 1522 76

Although mutated forms of ras are not associated with the majority of breast cancers (<5%), there is considerable experimental evidence that hyperactive Ras can promote breast cancer growth and development. Therefore, we determined whether Ras and Ras-responsive signaling pathways were activated persistently in nine widely studied human breast cancer cell lines. Although only two of the lines harbor mutationally activated ras, we found that five of nine breast cancer cell lines showed elevated active Ras-GTP levels that may be due, in part, to HER2 activation. Unexpectedly, activation of two key Ras effector pathways, the extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase and phosphatidylinositol 3'-kinase/AKT signaling pathways, was not always associated with Ras activation. Ras activation also did not correlate with invasion or the expression of proteins associated with tumor cell invasion (estrogen receptor alpha and cyclooxygenase 2). We then examined the role of Ras signaling in mediating resistance to matrix deprivation-induced apoptosis (anoikis). Surprisingly, we found that ERK and phosphatidylinositol 3'-kinase/AKT activation did not have significant roles in conferring anoikis resistance. Taken together, these observations show that Ras signaling exhibits significant cell context variations and that other effector pathways may be important for Ras-mediated oncogenesis, as well as for anoikis resistance, in breast cancer. Additionally, because ERK and AKT activation are not strictly associated with Ras activation, pharmacological inhibitors of these two signaling pathways may not be the best approach for inhibition of aberrant Ras function in breast cancer treatment.
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PMID:Involvement of Ras activation in human breast cancer cell signaling, invasion, and anoikis. 1523 70

Tissue transglutaminase (TGase) exhibits both a GTP binding/hydrolytic capability and an enzymatic transamidation activity. Increases in TGase expression and activation often occur in response to stimuli that promote cellular differentiation and apoptosis, yet the signaling mechanisms used by these stimuli to regulate TGase expression and activation and the role of TGase in these cellular processes are not well understood. Retinoic acid (RA) consistently induces TGase expression and activation, and it was shown recently that RA-induced TGase expression was inhibited in NIH3T3 mouse fibroblasts co-stimulated with epidermal growth factor (EGF). Here we investigate whether EGF also antagonized RA-induced TGase expression in breast cancer cells. We found that EGF stimulation affected TGase expression and activation very differently in these cancer cells. Not only did EGF fail to block RA-induced TGase expression, but also EGF alone was sufficient to potently up-regulate TGase expression and activation in SKBR3 cells, as well as MDAMB468 and BT-20 cells. Inhibiting phosphoinositide 3-kinase activity severely diminished the ability of EGF and RA to increase TGase protein levels, whereas a constitutively active form of phosphoinositide 3-kinase potentiated the induction of TGase expression by EGF in SKBR3 cells. Because EGF is an established antiapoptotic factor, we examined whether the protection afforded by EGF was dependent on its ability to up-regulate TGase activity in SKBR3 and BT-20 cells. Exposure of cells to a TGase inhibitor or expression of a dominant-negative form of TGase potently inhibited EGF-mediated protection from doxorubicin-induced apoptosis. Moreover, expression of exogenous TGase in SKBR3 cells mimicked the survival advantage of EGF, suggesting that TGase activation is necessary and sufficient for the antiapoptotic properties of EGF. These findings indicate for the first time that EGF can induce TGase expression and activation in human breast cancer cells and that this contributes to their oncogenic potential by promoting chemoresistance.
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PMID:Augmentation of tissue transglutaminase expression and activation by epidermal growth factor inhibit doxorubicin-induced apoptosis in human breast cancer cells. 1527 14

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