RGD Reference Report - Signatures associated with rejection or recurrence in HER-2/neu-positive mammary tumors. - Rat Genome Database

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Signatures associated with rejection or recurrence in HER-2/neu-positive mammary tumors.

Authors: Worschech, A  Kmieciak, M  Knutson, KL  Bear, HD  Szalay, AA  Wang, E  Marincola, FM  Manjili, MH 
Citation: Worschech A, etal., Cancer Res. 2008 Apr 1;68(7):2436-46.
RGD ID: 2298899
Pubmed: PMID:18381452   (View Abstract at PubMed)
PMCID: PMC2478745   (View Article at PubMed Central)
DOI: DOI:10.1158/0008-5472.CAN-07-6822   (Journal Full-text)

We have previously shown T-cell-mediated rejection of the neu-overexpressing mammary carcinoma cells (MMC) in wild-type FVB mice. However, following rejection of primary tumors, a fraction of animals experienced a recurrence of a neu antigen-negative variant (ANV) of MMC (tumor evasion model) after a long latency period. In the present study, we determined that T cells derived from wild-type FVB mice can specifically recognize MMC by secreting IFN-gamma and can induce apoptosis of MMC in vitro. Neu transgenic (FVBN202) mice develop spontaneous tumors and cannot reject it (tumor tolerance model). To dissect the mechanisms associated with rejection or tolerance of MMC tumors, we compared transcriptional patterns within the tumor microenvironment of MMC undergoing rejection with those that resisted it either because of tumor evasion/antigen loss recurrence (ANV tumors) or because of intrinsic tolerance mechanisms displayed by the transgenic mice. Gene profiling confirmed that immune rejection is primarily mediated through activation of IFN-stimulated genes and T-cell effector mechanisms. The tumor evasion model showed combined activation of Th1 and Th2 with a deviation toward Th2 and humoral immune responses that failed to achieve rejection likely because of lack of target antigen. Interestingly, the tumor tolerance model instead displayed immune suppression pathways through activation of regulatory mechanisms that included in particular the overexpression of interleukin-10 (IL-10), IL-10 receptor, and suppressor of cytokine signaling (SOCS)-1 and SOCS-3. These data provide a road map for the identification of novel biomarkers of immune responsiveness in clinical trials.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Experimental Mammary Neoplasms  ISOSocs1 (Mus musculus)2298899; 2298899mRNA:increased expression:mammary glandRGD 
Experimental Mammary Neoplasms  ISOSocs3 (Mus musculus)2298899; 2298899mRNA:increased expression:mammary glandRGD 
Experimental Mammary Neoplasms  IEP 2298899; 2298899mRNA:increased expression:mammary glandRGD 

Objects Annotated

Genes (Rattus norvegicus)
Socs1  (suppressor of cytokine signaling 1)
Socs3  (suppressor of cytokine signaling 3)

Genes (Mus musculus)
Socs1  (suppressor of cytokine signaling 1)
Socs3  (suppressor of cytokine signaling 3)

Genes (Homo sapiens)
SOCS1  (suppressor of cytokine signaling 1)
SOCS3  (suppressor of cytokine signaling 3)


Additional Information