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)

Ligands of the TGF-beta superfamily are unique in that they signal through transmembrane receptor serine-threonine kinases, rather than tyrosine kinases. The receptor complex couples to a signal transduction pathway involving a novel family of proteins, the Smads. On phosphorylation, Smads translocate to the nucleus where they modulate transcriptional responses. However, TGF-betas can also activate the mitogen-activated protein kinase (MAPK)4 pathway, and the different biological responses to TGF-beta depend to varying degrees on activation of either or both of these two pathways. The Smad pathway is a nexus for cross-talk with other signal transduction pathways and for modulation by many different interacting proteins. Despite compelling evidence that TGF-beta has tumor suppressor activity in the mammary gland, neither TGF-beta receptors nor Smads are genetically inactivated in human breast cancer, though receptor expression is reduced. Possible reasons are discussed in relation to the dual role of TGF-beta as tumor suppressor and oncogene.
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PMID:TGF-beta signaling in mammary gland development and tumorigenesis. 1146 53

Carcinoma cell lines are frequently refractory to transforming growth factor-beta (TGF beta)-mediated cell cycle arrest. Whether and how TGF beta signaling is disrupted in the majority of human tumors, however, remains unclear. To investigate whether TGF beta signaling might be disrupted by inactivation of the key signaling molecule, the TGF beta type I (T beta R-I) receptor, and whether or not T beta R-I inactivation is associated with late stage disease, we conducted a comprehensive structural analysis of the T beta R-I gene in fine-needle aspirates of 23 head-&-neck cancer metastases. We encountered 4 different mutations of T beta R-I, 3 of which have not been previously identified. In 1 case, we found a somatic intragenic 4-bp deletion predicting for a truncation of the receptor protein. This is the first example of a true loss-of-function mutation of T beta R-I in a human epithelial neoplasm. In 2 other cases, we identified missense mutations located between the juxtamembrane- and serine-threonine kinase domains. One of these resulted in an alanine-to-threonine substitution (A230T), which disrupts receptor signaling activity by causing rapid protein degradation within the endoplasmatic reticulum. This represents a novel mechanism of inactivation of a TGF beta signaling intermediate. Finally, we identified a serine-to-tyrosine substitution at codon 387 (S387Y) in a metastasis but not in the corresponding primary tumor. We had previously shown this S387Y mutant to be predominantly associated with breast cancer metastases and to have a diminished ability to mediate TGF beta-dependent signaling. In aggregate, these findings provide further support for the hypothesis that inactivation of the TGF beta signaling pathway occurs in a significant subset of human cancers.
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PMID:Novel inactivating mutations of transforming growth factor-beta type I receptor gene in head-and-neck cancer metastases. 1147 74

Phosphorylation on a serine or threonine residue preceding proline (Ser/Thr-Pro) is a key regulatory mechanism, and the conformation of certain phosphorylated Ser/Thr-Pro bonds is regulated specifically by the prolyl isomerase Pin1. Whereas the inhibition of Pin1 induces apoptosis, Pin1 is strikingly overexpressed in a subset of human tumours. Here we show that Pin1 regulates beta-catenin turnover and subcellular localization by interfering with its interaction with adenomatous polyposis coli protein (APC). A differential-display screen reveals that Pin1 increases the transcription of several beta-catenin target genes, including those encoding cyclin D1 and c-Myc. Manipulation of Pin1 levels affects the stability of beta-catenin in vitro. Furthermore, beta-catenin levels are decreased in Pin1-deficient mice but are increased and correlated with Pin1 overexpression in human breast cancer. Pin1 directly binds a phosphorylated Ser-Pro motif next to the APC-binding site in beta-catenin, inhibits its interaction with APC and increases its translocation into the nucleus. Thus, Pin1 is a novel regulator of beta-catenin signalling and its overexpression might contribute to the upregulation of beta-catenin in tumours such as breast cancer, in which APC or beta-catenin mutations are not common.
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PMID:Pin1 regulates turnover and subcellular localization of beta-catenin by inhibiting its interaction with APC. 1153 58

We have constructed a replication-deficient adenovirus encoding a nonphosphorylatable Thr(34)-->Ala mutant of the apoptosis inhibitor survivin (pAd-T34A) to target tumor cell viability in vitro and in vivo. Infection with pAd-T34A caused spontaneous apoptosis in cell lines of breast, cervical, prostate, lung, and colorectal cancer. In contrast, pAd-T34A did not affect cell viability of proliferating normal human cells, including fibroblasts, endothelium, or smooth muscle cells. Infection of tumor cells with pAd-T34A resulted in cytochrome c release from mitochondria, cleavage of approximately 46-kDa upstream caspase-9, processing of caspase-3 to the active subunits of approximately 17 and 19 kDa, and increased caspase-3 catalytic activity. When compared with chemotherapeutic regimens, pAd-T34A was as effective as taxol and considerably more effective than adriamycin in induction of tumor cell apoptosis and enhanced taxol-induced cell death. In three xenograft breast cancer models in immunodeficient mice, pAd-T34A suppressed de novo tumor formation, inhibited by approximately 40% the growth of established tumors, and reduced intraperitoneal tumor dissemination. Tumors injected with pAd-T34A exhibited loss of proliferating cells and massive apoptosis by in situ internucleosomal DNA fragmentation. These data suggest that adenoviral targeting of the survivin pathway may provide a novel approach for selective cancer gene therapy.
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PMID:Cancer gene therapy using a survivin mutant adenovirus. 1180 41

Several studies have investigated polymorphisms in CYP1A1 and breast cancer risk with inconsistent results. We have carried out a population based case-control study of the Thr461Asn and Ile462Val polymorphisms in CYP1A1 to clarify their importance in determining breast cancer susceptibility. A total of 1873 cases and 712 controls were genotyped for Thr461Asn and 1948 cases and 1355 controls were genotyped for Ile462Val. We have also investigated a putative interaction between smoking and CYP1A1 genotype and breast cancer risk using a case only study design. The genotype distribution of Thr461Asp in controls was close to that expected under Hardy-Weinberg equilibrium (HWE). We detected no significant differences in genotype frequencies between breast cancer cases and controls (P = 0.68). Compared with the Thr/Thr homozygotes there was no significant risk for either the Thr/Asp heterozygote [OR = 1.1 (95% CI 0.8-1.4)] or the Asp/Asp homozygote [OR = 0.4 (0.02-6.1)]. The genotype distribution of Ile462Val in controls was also close to that expected under HWE with no significant differences between breast cancer cases and the controls (P = 0.44). No significant risk was found for either the Ile/Val heterozygote [OR = 0.8 (0.6-1.1)] or the Val/Val homozygote [OR = 2.7 (0.3-24)] compared with the Ile/Ile homozygotes. Furthermore, subgroup analyses revealed no effect of age or menopausal status on genotypic risks, and we found no evidence for an interaction between genotype and smoking habit or alcohol consumption and susceptibility to breast cancer. We combined our data for the Ile462Val polymorphism with those from four other published studies, but even with >5000 subjects, none of the genotype-associated risks achieved statistical significance, and there was no consistent pattern to the risks associated with increasing Val allele dosage [Ile/Val OR = 0.9 (0.7-1.1), Val/Val OR = 2.3 (0.4-12), and Val carrier OR = 1.0 (0.9-1.1)].
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PMID:Polymorphisms in CYP1A1 and smoking: no association with breast cancer risk. 1169 41

A human protein termed p21-activated kinase 6 (PAK6), based on homology to the PAK family of serine/threonine kinases, was cloned as an AR interacting protein. PAK6 was a 75-kDa protein with a predicted N-terminal Cdc42/Rac interactive binding domain and a C-terminal kinase domain. PAK6 bound strongly to GTP-Cdc42 and weakly to GTP-Rac. In contrast to most PAKs, kinase activity was not stimulated by Cdc42 or Rac, but could be stimulated by AR binding. PAK6 interacted with the intact AR in a mammalian one-hybrid assay and bound in vitro, without ligand, to the hinge region between the AR DNA- and ligand-binding domains. PAK6 also bound to the ERalpha, and binding was enhanced by 4-hydroxytamoxifen. AR and ERalpha transcriptional activities were inhibited by PAK6 in transient transfections with episomal and integrated reporter genes. AR inhibition was not reversed by transfection with an activated Cdc42 mutant, Cdc42V12, which by itself also inhibited AR transactivation. Epitope-tagged PAK6 was primarily cytoplasmic in the absence or presence of AR and hormone. PAK6 transcripts were expressed most highly in brain and testis, with lower levels in multiple tissues including prostate and breast. PAK6 interaction provides a mechanism for cross-talk between steroid hormone receptors and Cdc42-mediated signal transduction pathways and could contribute to the effects of tamoxifen in breast cancer and in other tissues.
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PMID:AR and ER interaction with a p21-activated kinase (PAK6). 1177 41

Initial studies have identified TSP50 as a human testes-specific gene that is demethylated in breast cancer. In this study, we will present new data related to the TSP50 gene. We have found that the TSP50 gene product shares a similar enzymatic structure with many serine proteases. However, the most critical catalytic site, serine, has been replaced by threonine. Western analysis revealed that in human testes, the TSP50 antibody detected two closely positioned protein bands whose estimated molecular masses were 37 kDa, whereas in a large portion of breast cancer tissues, but not normal control tissues, only one band was present. Immunohistochemistry assays found TSP50 proteins located in the spermatocytes of human testes, whereas in situ hybridization and immunohistochemistry confirmed that gene activation in breast tumors took place in malignant mammary epithelial cells. These results suggested that the normal function of the TSP50 gene was involved in spermatogenesis, whereas the up-regulation of TSP50 in many breast cancer patients not only indicated that it might be a novel biomarker for this disease but also encouraged us to further explore the possibility of whether it was an oncogene.
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PMID:TSP50, a possible protease in human testes, is activated in breast cancer epithelial cells. 1178 90

Insulin-like growth factor I (IGF-1) is a well-established mitogen to many different cell types and is implicated in progression of a number of human cancers, notably breast cancer. The prolyl isomerase Pin1 plays an important role in cell cycle regulation through its specific interaction with proteins that are phosphorylated at Ser/Thr-Pro motifs. Pin1 knockout mice appear to have relatively normal development yet the Pin1(-/-)mouse embryo fibroblast (MEF) cells are defective in re-entering cell cycle in response to serum stimulation after G0 arrest. Here, we report that Pin1(-/-) MEF cells display a delayed cell cycle S-phase entry in response to IGF stimulation and that IGF-1 induces Pin1 protein expression which correlates with the induction of cyclin D1 and RB phosphorylation in human breast cancer cells. The induction of Pin1 by IGF-1 is mediated via the phosphatidylinositol 3-kinase as well as the MAP kinase pathways. Treatment of PI3K inhibitor LY294002 and the MAP kinase inhibitor PD098059, but not p38 inhibitor SB203580, effectively blocks IGF-1-induced upregulation of Pin1, cyclin D1 and RB phosphorylation. Furthermore, we found that Cyclin D1 expression and RB phosphorylation are dramatically decreased in Pin1(-/-) MEF cells. Reintroducing a recombinant adenovirus encoding Pin1 into Pin1(-/-) MEF cells restores the expression of cyclin D1 and RB phosphorylation. Thus, these data suggest that the mitogenic function of IGF-1 is at least partially linked to the induction of Pin1, which in turn stimulates cyclin D1 expression and RB phosphorylation, therefore contributing to G0/G1-S transition.
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PMID:IGF-1 induces Pin1 expression in promoting cell cycle S-phase entry. 1178 50

Genetic variability in DNA repair may contribute to hypersensitivity to ionizing radiation (IR) and susceptibility to breast cancer. We used samples collected from a clinic-based breast cancer case-control study to test the working hypothesis that amino acid substitution variants of DNA repair genes may contribute to prolonged cell-cycle delay following IR and breast cancer risk. Fluorescence-activated cell sorter (FACS) analysis was used to measure cell-cycle delay. PCR-restriction fragment length polymorphism (RFLP) assays were used to determine four genotypes of three DNA repair genes: XRCC1, 194 Arg/Trp and 399 Arg/Gln; XRCC3, 241 Thr/Met; and APE1, 148 Asp/Glu. The data showed that breast cancer patients had a significantly higher delay index than that of controls (P < 0.001); the means +/- SD for cases and controls were 36.0 +/- 13.1 (n = 118) and 31.4 +/- 11.5 (n = 225), respectively. There was a significant dose-response relationship between delay index, categorized into quartiles, and an increasing risk of breast cancer (crude odds ratios: 1.00, 1.00, 1.27, and 2.46, respectively; P(trend) = 0.002). In controls, prolonged cell-cycle delay was significantly associated with the number of variant alleles in APE1 Asp148Glu and XRCC1 Arg399Gln genotypes (P(trend) = 0.001). Although larger studies are needed to validate the results, our data suggest that an inherited hypersensitivity to IR may contribute to human breast carcinogenesis.
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PMID:Genetic regulation of ionizing radiation sensitivity and breast cancer risk. 1192 Nov 91

We found that PPM1D, encoding a serine/threonine protein phosphatase, lies within an epicenter of the region at 17q23 that is amplified in breast cancer. We show that overexpression of this gene confers two oncogenic phenotypes on cells in culture: attenuation of apoptosis induced by serum starvation and transformation of primary cells in cooperation with RAS.
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PMID:Oncogenic properties of PPM1D located within a breast cancer amplification epicenter at 17q23. 1202 84


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