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)

The human P-glycoprotein (Pgp) is a drug-efflux pump responsible for innate or acquired multidrug resistance in many cancers. Pgp contains a unique approximately 75 amino acid long linker region in its middle, which is critically important for its drug transport and ATPase functions. To identify cellular proteins that bind to this linker region and modulate Pgp function, a yeast two-hybrid analysis was carried out. This procedure identified RNF2 (RING finger protein 2), an E3 ubiquitin ligase, as a prominent Pgp-interacting protein. Co-expression of RNF2 with Pgp in Sf9 insect cells resulted in decreased ATPase activity and proteolytic protection of the transporter protein. Immunoprecipitation experiments confirmed the physical interaction between these two proteins. Confocal microscopy showed the presence of RNF2 in the cytoplasm of the Pgp-negative, drug-sensitive MCF-7 breast cancer cells. However, it was undetectable in the Pgp-positive and drug-resistant MCF-7 cells. We suggest that RNF2 regulates the cellular abundance of Pgp, and plays a key role in the development of cancer drug resistance through its own down-regulation.
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PMID:RNF2 interacts with the linker region of the human P-glycoprotein. 1708 79

Osteopontin that associates with metabolism of calcium is one of the important factors in the development and prognosis of human breast cancer. The aim of this study was to detect potential binding partners of osteopontin to illustrate its functional mechanism. By screening a human breast cDNA library with a bacterial two-hybrid system, apolipoprotein D was isolated as a novel interacting protein of osteopontin. This interaction was confirmed by mammalian two-hybrid assay and co-immunoprecipitation. To elucidate the influence of ApoD on cellular neoplastic specifications, adhesion, soft agar, invasion and MTT growth assays were performed with Rama37 cells. The results revealed that expression of apolipoprotein D in Rama37 cells could significantly inhibit the malignant phenotype in osteopontin-transformed Rama37 cells. These findings provide better knowledge of the osteopontin signaling pathway and suggest that apolipoprotein D could be a prospective therapeutic agent for human breast and/or other carcinomas.
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PMID:Identification of apolipoprotein D as a novel inhibitor of osteopontin-induced neoplastic transformation. 1708 1

CCAAT/enhancer-binding proteins (C/EBPs) are transcriptional regulators implicated in cell proliferation, differentiation, survival, and tumorigenesis. Their biological activities require interactions with several protein partners. This report presents insights from in silico analysis aimed at identifying phosphorylation-dependent protein recognition motifs in C/EBPs. (1) All C/EBP variants contain intrinsically disordered Ser/Thr- and Pro-rich segments with potential docking sites for WW and Polo-box domains of prolyl isomerase Pin1 and Polo-like kinases (Plks), respectively. (2) Consensus phosphorylation sequences for Plks are located in a highly conserved region of transactivation domains, suggesting that Plks might modulate transcriptional activities of C/EBPs in a cell cycle-dependent manner. (3) Phosphorylation at these positions, as well as at conserved Ser in the extended basic region, would create phosphoserine-containing motifs (pSXXF/Y/I/L), which could be recognized by BRCT repeats containing proteins such as the PAX-transactivation-domain-interacting protein (PTIP), and the breast cancer-associated protein (BRCA1). Proteins containing BRCT domains serve as scaffolds, mediating protein-protein interactions and formation of functional multiprotein complexes involved in DNA repair and cell cycle control. These findings add a new perspective to studies aimed at elucidation of molecular mechanisms underlying the diverse functions of C/EBPs.
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PMID:Phospho-dependent protein recognition motifs contained in C/EBP family of transcription factors: in silico studies. 1710 35

MAPK-interacting protein kinases 1 and 2 (MNK1 and MNK2) function downstream of p38 and ERK MAPK, but there are large gaps in our knowledge of how MNKs are regulated and function. As proteins activated in the HER2/Ras/Raf/ERK pathway, the MNKs are of potential interest in HER2-overexpressing cancers. We utilized a panel of breast cell lines (HCC1419, AU565, SKBR3, MCF7, and MCF10A), three of which overexpress HER2, to characterize the amounts and activation status of MNKs and other pathway enzymes (ERKs and RSKs) in these cells. We generated a phosphospecific antibody to Thr(P)-214 in the T-loop of MNKs and found that phosphorylations of both Thr-209 and Thr-214 in human MNK1 are required for activation. Increased phosphorylation and activity of the MNKs correlate with HER2 overexpression, and inhibition of the MNKs reduces colony formation in soft agar. Our work identifies the MNKs as potential therapeutic targets for breast cancer treatments.
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PMID:MNK1 and MNK2 regulation in HER2-overexpressing breast cancer lines. 1713 Jan 35

Tumors can become lethal when they progress from preinvasive lesions to invasive carcinomas. Here, we identify candidate tumor progression genes using gene array analysis of preinvasive and invasive tumors from mice, which were then evaluated in human cancers. Immediate early response protein IEX-1, small stress protein 1 (HSPB8), and tumor necrosis factor-associated factor-interacting protein mRNAs displayed higher expression levels in invasive lesions than in preinvasive lesions using samples obtained by laser capture microdissection (LCM) from transgenic erbB2, ras, and cyclin D1 mice. LCM-isolated tissues from patient-matched normal, ductal carcinoma in situ, and invasive ductal carcinoma revealed similar increased expression in invasive human cancers compared with preinvasive and normal samples. These genes induced anchorage independence, increased cell proliferation, and protected against apoptosis, singly or in collaboration with erbB2. Surprisingly, they were all up-regulated by 17beta-estradiol and cyclin D1, and cyclin D1 overexpression increased p300/CBP binding to their promoters, supporting the model that cyclin D1-estrogen receptor (ER) coactivator interactions may be important to its role in ER-positive breast cancer. Additionally, an irreversible dual kinase inhibitor of ErbB signaling inhibited expression of the same genes. The up-regulation of genes contributing to increased invasiveness of ER-positive cancers offers a novel explanation for the contribution of cyclin D1 to a worse prognosis in ER-positive cancers. As targets of estrogen, cyclin D1, and erbB2 signaling, these candidates offer insights into the nature of the second events involved in breast cancer progression, regulatory events contributing to invasion, and potential targets of combined inhibition of hormone and growth factor signaling pathways.
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PMID:Identification of cyclin D1- and estrogen-regulated genes contributing to breast carcinogenesis and progression. 1717 59

Vitamin D receptor interacting protein (DRIP150) coactivates estrogen receptor alpha (ERalpha)-mediated transactivation in breast cancer cell lines transfected with a construct (pERE(3)) containing three estrogen responsive elements (EREs). In this study, we show that DRIP150 also coactivates ERalpha/Sp1-mediated transactivation in ZR-75, MCF-7, and MDA-MB-231 breast cancer cells transfected with a construct (pSp1(3)) containing three consensus GC-rich motifs. Studies on coactivation of wild-type and variant ERalpha/Sp1 by DRIP150 indicates that the DNA-binding domain and helix 12 in the ligand binding domain of ERalpha are required and the coactivation response is squelched by overexpressing an NR-box peptide that contains two LXXLL motifs from GRIP2. In contrast, coactivation of ERalpha/Sp1 by wild-type and mutant DRIP150 expression plasmids show that coactivation of ERalpha/Sp1 by DRIP150 is independent of the NR-boxes. Deletion analysis of DRIP150 demonstrates that coactivation requires an alpha-helical NIFSEVRVYN (amino acids 795-804) motif within 23 amino acid sequence (789-811) in the central region of DRIP150 and similar results were obtained for coactivation of ERalpha by DRIP150. Thus, although different domains of ERalpha are required for hormone-dependent activation of ERalpha and ERalpha/Sp1, coactivation of these transcription factors by DRIP150 requires the alpha-helical amino acids 795-804. This is the first report of a coactivator that enhances ERalpha/Sp1-mediated transactivation in breast cancer cells.
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PMID:Coactivation of estrogen receptor alpha (ER alpha)/Sp1 by vitamin D receptor interacting protein 150 (DRIP150). 1730 56

Mutations in the breast cancer susceptibility gene 1 (BRCA1) are associated with an increased risk of breast and ovarian cancers. BRCA1 participates in the cellular DNA damage response. We report the identification of receptor-associated protein 80 (RAP80) as a BRCA1-interacting protein in humans. RAP80 contains a tandem ubiquitin-interacting motif domain, which is required for its binding with ubiquitin in vitro and its damage-induced foci formation in vivo. Moreover, RAP80 specifically recruits BRCA1 to DNA damage sites and functions with BRCA1 in G2/M checkpoint control. Together, these results suggest the existence of a ubiquitination-dependent signaling pathway involved in the DNA damage response.
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PMID:Ubiquitin-binding protein RAP80 mediates BRCA1-dependent DNA damage response. 1752 26

The ribosomal acidic P0 protein, an essential component of the eukaryotic ribosomal stalk, was found to interact with the helix-loop-helix protein human Grap2 and cyclin D interacting protein (GCIP)/D-type cyclin-interacting protein 1/human homolog of MAID protein. Using in vivo and in vitro binding assays, we show that P0 can interact with the N and C termini of GCIP via its N-terminal 39-114 amino-acid residues. Although the P0-GCIP complex was detected mainly in cytoplasmic fraction, polysome profile analysis indicated that the P0-GCIP complex did not coelute with either polysomes or 60S ribosomes, suggesting that GCIP associates with the free form of P0 in the cytoplasm. Transfection of GCIP into MCF-7 cells resulted in decreased levels of pRb phosphorylation. Cotransfection of P0 with GCIP, however, resulted in GCIP-mediated reduction of pRb phosphorylation level which was repressed by P0. Furthermore, overexpression of P0 in breast cancer and hepatocellular cancer cell lines promoted cell growth and colony formation compared to control transfectants. Overexpression of P0 also increased cyclin D1 expression and phosphorylation of pRb at Ser780. Interestingly, P0 mRNA was overexpressed in 12 of 20 pairs of breast cancer/ normal breast specimens (60%). Together, these data indicate that P0 overexpression may cause tumorigenesis in breast and liver tissues at least in part by inhibiting GCIP-mediated tumor suppression.
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PMID:Ribosomal phosphoprotein P0 interacts with GCIP and overexpression of P0 is associated with cellular proliferation in breast and liver carcinoma cells. 1762 Dec 66

The product of the breast cancer-1 gene, BRCA1, plays a crucial part in the DNA damage response through its interactions with many proteins, including BACH1, CtIP and RAP80. Here we identify a coiled-coil domain-containing protein, CCDC98, as a BRCA1-interacting protein. CCDC98 colocalizes with BRCA1 and is required for the formation of BRCA1 foci in response to ionizing radiation. Moreover, like BRCA1, CCDC98 has a role in radiation sensitivity and damage-induced G2/M checkpoint control. Together, these results suggest that CCDC98 is a mediator of BRCA1 function involved in the mammalian DNA damage response.
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PMID:CCDC98 is a BRCA1-BRCT domain-binding protein involved in the DNA damage response. 1764 22

Homologous recombination (HR) is critical for maintaining genome stability through precise repair of DNA double-strand breaks (DSBs) and restarting stalled or collapsed DNA replication forks. HR is regulated by many proteins through distinct mechanisms. Some proteins have direct enzymatic roles in HR reactions, while others act as accessory factors that regulate HR enzymatic activity or coordinate HR with other cellular processes such as the cell cycle. The breast cancer susceptibility gene BRCA2 encodes a critical accessory protein that interacts with the RAD51 recombinase and this interaction fluctuates during the cell cycle. We previously showed that a BRCA2- and p21-interacting protein, BCCIP, regulates BRCA2 and RAD51 nuclear focus formation, DSB-induced HR and cell cycle progression. However, it has not been clear whether BCCIP acts exclusively through BRCA2 to regulate HR and whether BCCIP also regulates the alternative DSB repair pathway, non-homologous end joining. In this study, we found that BCCIP fragments that interact with BRCA2 or with p21 each inhibit DSB repair by HR. We further show that transient down-regulation of BCCIP in human cells does not affect non-specific integration of transfected DNA, but significantly inhibits homology-directed gene targeting. Furthermore, human HT1080 cells with constitutive down-regulation of BCCIP display increased levels of spontaneous single-stranded DNA (ssDNA) and DSBs. These data indicate that multiple BCCIP domains are important for HR regulation, that BCCIP is unlikely to regulate non-homologous end joining, and that BCCIP plays a critical role in resolving spontaneous DNA damage.
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PMID:BCCIP regulates homologous recombination by distinct domains and suppresses spontaneous DNA damage. 1794 33


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