32 research outputs found
Heterologous Tissue Culture Expression Signature Predicts Human Breast Cancer Prognosis
BACKGROUND: Cancer patients have highly variable clinical outcomes owing to many factors, among which are genes that determine the likelihood of invasion and metastasis. This predisposition can be reflected in the gene expression pattern of the primary tumor, which may predict outcomes and guide the choice of treatment better than other clinical predictors. METHODOLOGY/PRINCIPAL FINDINGS: We developed an mRNA expression-based model that can predict prognosis/outcomes of human breast cancer patients regardless of microarray platform and patient group. Our model was developed using genes differentially expressed in mouse plasma cell tumors growing in vivo versus those growing in vitro. The prediction system was validated using published data from three cohorts of patients for whom microarray and clinical data had been compiled. The model stratified patients into four independent survival groups (BEST, GOOD, BAD, and WORST: log-rank test p = 1.7×10(−8)). CONCLUSIONS: Our model significantly improved the survival prediction over other expression-based models and permitted recognition of patients with different prognoses within the estrogen receptor-positive group and within a single pathological tumor class. Basing our predictor on a dataset that originated in a different species and a different cell type may have rendered it less sensitive to proliferation differences and endowed it with wide applicability. SIGNIFICANCE: Prognosis prediction for patients with breast cancer is currently based on histopathological typing and estrogen receptor positivity. Yet both assays define groups that are heterogeneous in survival. Gene expression profiling allows subdivision of these groups and recognition of patients whose tumors are very unlikely to be lethal and those with much grimmer outlooks, which can augment the predictive power of conventional tumor analysis and aid the clinician in choosing relaxed vs. aggressive therapy
Gene expression profiling reveals different pathways related to Abl and other genes that cooperate with c-Myc in a model of plasma cell neoplasia
<p>Abstract</p> <p>Background</p> <p>To elucidate the genes involved in the neoplastic transformation of B cells, global gene expression profiles were generated using Affymetrix U74Av2 microarrays, containing 12,488 genes, for four different groups of mouse B-cell lymphomas and six subtypes of pristane-induced mouse plasma cell tumors, three of which developed much earlier than the others.</p> <p>Results</p> <p>Unsupervised hierarchical cluster analysis exhibited two main sub-clusters of samples: a B-cell lymphoma cluster and a plasma cell tumor cluster with subclusters reflecting mechanism of induction. This report represents the first step in using global gene expression to investigate molecular signatures related to the role of cooperating oncogenes in a model of Myc-induced carcinogenesis. Within a single subgroup, e.g., ABPCs, plasma cell tumors that contained typical T(12;15) chromosomal translocations did not display gene expression patterns distinct from those with variant T(6;15) translocations, in which the breakpoint was in the <it>Pvt-1 </it>locus, 230 kb 3' of c-<it>Myc</it>, suggesting that c-<it>Myc </it>activation was the initiating factor in both. When integrated with previously published Affymetrix array data from human multiple myelomas, the IL-6-transgenic subset of mouse plasma cell tumors clustered more closely with MM1 subsets of human myelomas, slow-appearing plasma cell tumors clustered together with MM2, while plasma cell tumors accelerated by v-Abl clustered with the more aggressive MM3-MM4 myeloma subsets. Slow-appearing plasma cell tumors expressed <it>Socs1 </it>and <it>Socs2 </it>but v-<it>Abl</it>-accelerated plasma cell tumors expressed 4–5 times as much. Both v-<it>Abl</it>-accelerated and non-v-<it>Ab</it>l-associated tumors exhibited phosphorylated STAT 1 and 3, but only v-Abl-accelerated plasma cell tumors lost viability and STAT 1 and 3 phosphorylation when cultured in the presence of the v-Abl kinase inhibitor, STI-571. These data suggest that the Jak/Stat pathway was critical in the transformation acceleration by v-Abl and that v-Abl activity remained essential throughout the life of the tumors, not just in their acceleration. A different pathway appears to predominate in the more slowly arising plasma cell tumors.</p> <p>Conclusion</p> <p>Gene expression profiling differentiates not only B-cell lymphomas from plasma cell tumors but also distinguishes slow from accelerated plasma cell tumors. These data and those obtained from the sensitivity of v-Abl-accelerated plasma cell tumors and their phosphorylated STAT proteins indicate that these similar tumors utilize different signaling pathways but share a common initiating genetic lesion, a c-<it>Myc</it>-activating chromosome translocation.</p
Multiple isoforms of protein kinase C in lymphocytes and airway smooth muscle of guinea pig
280-284The isoenzyme pattern of protein kinase C (PKC) in lymphocytes and
airway smooth muscles (ASM) was examined by Wes tern blot using commercially
available monoclonal
antibodies. The results showed the presence of PKC α, β, γ, ε, η, μ and
ζ in lymphocytes and PKC α, γ, ε, η and ζ in ASM. The unexpected feature
was the presence of PKC γ in both lymphocytes and ASM of guinea pigs.
Expression of this PKC isoform is usually restricted to tissues in the central
nervous system or spinal cord. Expression of PKC δ, θ, λ and τ was not detected
in either lymphocytes or ASM.
Induction of plasmacytomas that secrete monoclonal anti-peptide antibodies by retroviral transformation.
ABL-MYC, a retrovirus that coexpresses v-abl and c-myc, was used to infect six BALB/c mice that had been immunized twice with a KLH-conjugated peptide that consisted of the 18 carboxyterminal amino acids of protein kinase C-η (PKC-η). All mice developed transplantable, monoclonal plasmacytomas, and five out of six plasmacytomas secreted antigen-specific antibodies, even after transplantation. All these antibodies recognized PKC-η on Western blots of crude cell lysates and did not cross react with other isoforms of the PKC family
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Induction of Hematopoietic Tumors Using a Viral Construct Containing c-myc cDNA from Normal Mouse Spleen
Deregulated expression of the c-myc protooncogene is assumed to be a major contributing factor to the development of plasmacytomas in pristane-primed BALB/c mice (reviewed in Potter, 1986) and murine T cell lymphomas induced by AKR and Moloney murine leukemia viruses (MuLV) (Steffen 1984, Selden et al. 1984, Li et al. 1 984, Corcoran et al. 1984). Studies on the c-myc expression in plasmacytomas suggest that myc can be deregulated by a variety of mechanisms. These include stabilization of the myc message due to an altered transcriptional unit (Piechaczyk et a1. 1985), removal of cis-acting regulatory sequences (Yang et al. 1985) and augmentation of transcriptional activity resulting from apposed IgH enhancer sequences (Corcoran, 1985). These studies provide substantial inferential support for the view that aberrant expression of myc is central to the trarisformation of murine plasma cells and T cells but direct evidence to buttress this argument has been lacking. Efforts to develop this evidence have taken several complementary directions, all resulting in abnormally high levels of myc expression in somatic cells. These include the development of transgenic mice with murine or human c-myc genes driven by selected promoter/enhancer sequences (Stewart et al. 1 984; Adams et al. 1986) or infection of mice with recombinant murine retroviruses containing avian v-myc genes (Morse et al. 1986; Potter et al. 1986). The avian v-myc genes are known to contain numerous coding region mutations in comparison to normal avian c-myc sequences and also differ from normal murine c-myc genes (Papas and Lautenberger 1985). Since sequence differences among avian v-myc genes appear to contribute to variations in their oncogenic potentials (Enrietto et al. 1984), we wished to determine if overexpression of a normal murine c-myc gene in mice would result in the development of tumors. This report describes the features of two new recombinant murine retroviruses containing normal mouse c-myc coding sequences and the results obtained when pseudotypes of these viruses were used to infect adult, pristane-primed BALB/c mice