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)

Two related Rho GTPase-activating proteins, DLC-1 (deleted in liver cancer 1) and DLC-2, are emerging as bona fide tumor suppressor genes that inhibit cancer cell growth. In this report, we characterized a gene on chromosome Xq13 that encodes DLC-3 (also known as KIAA0189 and STARD8), a third member of the DLC family. The DLC-3 gene has transcripts with alternative 5' ends, one of which, DLC-3alpha, encodes an 1103-amino acid polypeptide highly similar to DLC-1 and DLC-2. A second isoform (DLC-3beta) would yield a protein lacking the N-terminal sterile alpha motif domain. The DLC-3 gene is widely expressed in normal tissues, but DLC-3 mRNA levels were low or absent in a significant number of breast, ovarian, liver and prostate cancer cell lines. Using a cancer profiling array to compare matched tumor and normal human tissues, downregulation of DLC-3 mRNA was observed in kidney, lung, ovarian, uterine and breast cancer samples. By quantitative reverse transcriptase-polymerase chain reaction, DLC-3 expression was reduced in primary prostate carcinomas relative to normal prostate tissue. Transfection of human breast and prostate cancer cells with a DLC-3alpha expression vector inhibited cell proliferation, colony formation and growth in soft agar. These results indicate that deregulation of DLC-3 may contribute to breast and prostate tumorigenesis.
 ...
PMID:Deleted in liver cancer 3 (DLC-3), a novel Rho GTPase-activating protein, is downregulated in cancer and inhibits tumor cell growth. 1729 65

Estrogen and structurally related molecules play critical roles in breast cancer. We reported that resveratrol (50 microM), an estrogen-like phytosterol from grapes, acts in an antiestrogenic manner in breast cancer cells to reduce cell migration and to induce a global and sustained extension of actin structures called filopodia. Herein, we report that resveratrol-induced filopodia formation is time-dependent and concentration-dependent. In contrast to resveratrol at 50 microM, resveratrol at 5 microM acts in a manner similar to estrogen by increasing lamellipodia, as well as cell migration and invasion. Because Rho GTPases regulate the extension of actin structures, we investigated a role for Rac and Cdc42 in estrogen and resveratrol signaling. Our results demonstrate that 50 microM resveratrol decreases Rac and Cdc42 activity, whereas estrogen and 5 microM resveratrol increase Rac activity in breast cancer cells. MDA-MB-231 cells expressing dominant-negative Cdc42 or dominant-negative Rac retain filopodia response to 50 microM resveratrol. Lamellipodia response to 5 microM resveratrol, estrogen, or epidermal growth factor is inhibited in cells expressing dominant-negative Rac, indicating that Rac regulates estrogen and resveratrol (5 microM) signaling to the actin cytoskeleton. These results indicate that signaling to the actin cytoskeleton by low and high concentrations of resveratrol may be differentially regulated by Rac and Cdc42.
 ...
PMID:Estrogen and resveratrol regulate Rac and Cdc42 signaling to the actin cytoskeleton of metastatic breast cancer cells. 1735 11

Environmental substances seem to be involved in the etiology of breast cancers. Many studies have found an association between human cancer and exposure to agricultural pesticides such as the organophosphorous pesticides. Parathion is a cholinesterase inhibitor that induces the hydrolysis of body choline esters, including acetylcholine at cholinergic synapses. The primary target of action in insects is the nervous system whereby pesticides inhibit the release of the enzyme acetylcholinesterase at the synaptic junction. Atropine is a parasympatholytic alkaloid used as an antidote to acetylcholinesterase inhibitors. The aim of this study was to determine the effect of parathion and atropine on cell transformation of human breast epithelial cells in vitro. These studies showed that parathion alone was able to induce malignant transformation of an immortalized human breast epithelial cell line, MCF-10F as indicated by increased cell proliferation, anchorage independency and invasive capabilities. There was also an increase in c-kit, Trio, Rho-A, Rac-3, EGFR, Notch-4, Dvl-2, Ezrin, beta catenin and mutant p53 protein expression in the parathion-treated cells. However, atropine significantly inhibited this increase. In a human cell cycle array of 96 genes, 13 of them were altered by parathion treatment. Among the genes affected were the cyclins, such as cyclin D3, the cyclin-dependent kinases (CDKs) such as CDK41 and the minichromosome maintenance deficient (MCM) MCM2 and MCM3. It is suggested that parathion influences human breast epithelial cell transformation and is an initiator factor in the transformation process in breast cancer.
 ...
PMID:Gene expression signature of parathion-transformed human breast epithelial cells. 1739 78

Overexpression of HER family members is a well established prognostic factor and identifies potential targets for antibody-based receptor blocking strategies. While several studies have analyzed the expression of HER2 and other HER-family members in malignant tumors, considerably less is known about their expression and activation in non-involved breast tissue from breast cancer patients. We have therefore investigated the differential expression of EGFR, HER2, and their tyrosine-kinase activated forms (ptyr-1248 Her-2 and ptyr-845 EGFR) in 63 tumor specimen containing: a) malignant epithelium, b) in non-malignant tissue located at the peritumoral margin, and c) in uninvolved breast tissue obtained from tissue distant from the tumor. Using immunohistochemistry (IHC), we found significantly higher HER2 protein expression levels in malignant epithelium than in marginal and peripheral non-malignant epithelium (p=1.3 x 10(-10) Fisher's exact test). Epithelial EGFR expression did not differ between the three tissue types, but stromal EGFR protein was significantly more common in marginal and peripheral tissues when compared to tumor tissues (p=0.008, Fisher's exact test). When analyzing activated receptor forms, we found epithelial ptyr-1248 HER2 expression in one tumoral, one marginal and one peripheral sample. We did not observe ptyr-845 EGFR in any of the samples analyzed. We found a significant overall correlation between epithelial and stromal EGFR expression (r=0.442; p<0.0001; Spearman's Rho), and between stromal EGFR expression and normal tissue type (r=0.170; p<0.02; Spearman's Rho). Epithelial HER2 expression and normal tissue type (r=0.492; p<0.0001; Spearman's Rho) were inversely correlated. Taken together, we have observed a differential expression pattern of EGFR, HER2, and activated HER2 that is dependent on the spatial relation to a malignant tumor. Our findings of decreased intratumoral EGFR expression and the absence of activated EGFR suggests that, in contrast to HER2, EGFR inhibition might not be an ideal target for antibody therapy.
 ...
PMID:Differential spatial expression and activation pattern of EGFR and HER2 in human breast cancer. 1761 48

Cancer of the breast is the most common form of malignant disease occurring among women of the western world and environmental substances seem to be involved in the etiology of this disease. Many studies have found an association between human cancer and exposure to agricultural pesticides and among them parathion, the organophosphorous pesticide used in agriculture to control mosquito plagues. The association between breast cancer and prolonged exposure to estrogens suggests that this hormone also may have a role in such process. However, the causative factors for breast carcinogenesis remain an enigma. The objective of this study was to determine the effects of 17beta-estradiol (E2) and parathion on cell transformation of human breast epithelial cells in vitro. The results of this study showed that parathion alone and in combination with E2 induced malignant transformation of an immortalized human breast epithelial cell line, MCF-10F, and the malignant feature was confirmed by anchorage independency and invasive capabilities. Parathion alone efficiently elevated the expression of EGFR, c-Kit, Trio, Rac 3, Rho-A, and mutant p53 proteins. Analysis of gene expression using commercially available human cell cycle array revealed transcriptional alterations in 22 out of a total of 96 genes. Among them, nine genes involved in the regulation of cell cycle were altered. These included cyclins (A1, A2, C, G1, G2, and H), cyclin-dependent kinases (CDKs), and minichromosome maintenance deficient (MCM). Results suggest that parathion has the potency to cause malignant transformation of breast epithelial cells through modulation of expression of cell cycle regulated genes.
 ...
PMID:Gene and protein expressions induced by 17beta-estradiol and parathion in cultured breast epithelial cells. 1762 25

We have previously reported that expression of SIRPalpha1/SHPS-1 was strongly suppressed in v-Src-transformed cells and its forced expression resulted in the suppression of anchorage-independent growth of the cells [K. Machida, S. Matsuda, K. Yamaki, T. Senga, A.A. Thant, H. Kurata, K. Miyazaki, K. Hayashi, T. Okuda, T. Kitamura, T. Hayakawa, M. Hamaguchi, v-Src suppresses SHPS-1 expression via the Ras-MAP kinase pathway to promote the oncogenic growth of cells, Oncogene 19 (2000) 1710-1718]. We examined the effect of human SIRPalpha1 expression in breast cancer cell lines, Hs578T and MCF7, and compared with the effect of SIRPalpha2 expression in Hs578T. Forced expression of either SIRPalpha1 or SIRPalpha2 did not perturb the growth of Hs578T in a conventional attached condition. Their expression, however, enforced the actin stress fiber formation and induced activation of Rho, but not Rac, in Hs578T cells. Moreover, forced expression of either SIRPalpha1 or SIRPalpha2 displayed distinct suppressive effect on the anchorage-independent growth of Hs578T cells. Similarly, forced expression of SIRPalpha1 in MCF7 specifically suppressed the anchorage-independent growth of the cells. Taken together, our results strongly suggest the function of SIRPalpha1 and 2 as type II tumor suppressors for human breast carcinoma.
 ...
PMID:SIRPalpha1 and SIRPalpha2: their role as tumor suppressors in breast carcinoma cells. 1763 76

Estrogen receptor alpha (ER alpha) is a ligand-activated transcription factor that regulates expression of estrogen-responsive genes. Upon binding of the ligand-occupied ER alpha to estrogen response elements (EREs) in DNA, the receptor interacts with a variety of coregulatory proteins to modulate transcription of target genes. We have isolated and identified a number of proteins associated with the DNA-bound ER alpha. One of these proteins, Rho guanosine diphosphate (GDP) dissociation inhibitor alpha (RhoGDI alpha), is a negative regulator of the Rho family of GTP-binding proteins. In this study, we demonstrate that endogenously expressed RhoGDI alpha is present in the nucleus as well as the cytoplasm of MCF-7 breast cancer cells, and that RhoGDI alpha binds directly to ER alpha, alters the ER alpha-ERE interaction, and influences the ability of ER alpha to regulate transcription of a heterologous estrogen-responsive reporter plasmid in transient transfection assays as well as endogenous, estrogen-responsive genes in MCF-7 cells. Our studies suggest that, in addition to the activity of RhoGDI alpha in the cytoplasm, it also influences ER alpha signaling in the nucleus.
 ...
PMID:Rho GDP dissociation inhibitor alpha interacts with estrogen receptor alpha and influences estrogen responsiveness. 1790 65

Abelson interactor protein-1 (ABI-1) is an adaptor protein involved in actin reorganization and lamellipodia formation. It forms a macromolecular complex containing Hspc300/WASP family verprolin-homologous proteins 2/ABI-1/nucleosome assembly protein 1/PIR121 or Abl/ABI-1/WASP family verprolin-homologous proteins 2 in response to Rho family-dependent stimuli. Due to its role in cell mobility, we hypothesized that ABI-1 has a role in invasion and metastasis. In the present study, we found that weakly invasive breast cancer cell lines (MCF-7, T47D, MDA-MB-468, SKBR3, and CAMA1) express lower levels of ABI-1 compared with highly invasive breast cancer cell lines (MDA-MB-231, MDA-MB-157, BT549, and Hs578T), which exhibit high ABI-1 levels. Using RNA interference, ABI-1 was stably down-regulated in MDA-MB-231, which resulted in decreased cell proliferation and anchorage-dependent colony formation and abrogation of lamellipodia formation on fibronectin. Down-regulation of ABI-1 decreased invasiveness and migration ability and decreased adhesion on collagen IV and actin polymerization in MDA-MB-231 cells. Additionally, compared with control parental cells, ABI-1 small interfering RNA-transfected cells showed decreased levels of phospho-PDK1, phospho-Raf, phospho-AKT, total AKT, and AKT1. These data suggest that ABI-1 plays an important role in the spread of breast cancer and that this role may be mediated via the phosphatidylinositol 3-kinase pathway.
 ...
PMID:Abelson interactor protein-1 positively regulates breast cancer cell proliferation, migration, and invasion. 1795 3

Small GTPase Rho signaling pathways regulate the growth, motility, invasion and metastasis of breast cancer cells. Aberrant Rho signaling, as results from alterations in the levels of Rho GTPase proteins, the status of activation, and the abundance of effector proteins, is found in breast cancers. Alterations of Rho signaling particularly impact the cytoskeleton, whose organization and reorganization underpin the motility of breast cancer cells during the invasive growth and metastasis of breast cancer. Progress is being made to elucidate the underlying mechanisms by which Rho GTPases activate the downstream signaling effectors. Further investigations are required for development of novel tumor therapeutic strategies targeting the Rho GTPase signaling pathways to treat breast cancer.
 ...
PMID:Role of Rho GTPases in breast cancer. 1798 86

Although the net benefits of tamoxifen in adjuvant breast cancer therapy have been proven, the recurrence of the cancer in an aggressive and hormone independent form has been highly problematic. We previously demonstrated the important role mitochondrial DNA (mtDNA) plays in hormone-independence in prostate cancer. Here, the role of mtDNA in breast cancer progression was investigated. We established hydroxytamoxifen (4-OHT) resistant HTRMCF by growing MCF-7, human breast adenocarcinoma cells, in the presence of 4-OHT. HTRMCF was cross-resistant to 4-OHT and ICI182,780 concurrent with the depletion of mtDNA. To further investigate the role of mtDNA depletion, MCF-7 was depleted of mtDNA by treatment with ethidium bromide. MCF Rho 0 was resistant to both 4-OHT and ICI182,780. Furthermore, cybrid (MCFcyb) prepared by fusion MCF Rho 0 with platelet to transfer mtDNA showed susceptibility to antiestrogen. Surprisingly, after withdrawal of 4-OHT for 8 weeks, HTRMCF and their clones became susceptible to both drugs concurrent with a recovery of mtDNA. Herein, our results substantiated the first evidence that the depletion of mtDNA induced by hormone therapy triggers a shift to acquired resistance to hormone therapy in breast cancer. In addition, we showed that mtDNA depletion can be reversed, rendering the cancer cells susceptible to antiestrogen. The fact that the hormone independent phenotype can be reversed should be a step toward more effective treatments for estrogen-responsive breast cancer.
 ...
PMID:Induction of acquired resistance to antiestrogen by reversible mitochondrial DNA depletion in breast cancer cell line. 1799 Mar 20


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