Identification of an Integrated SV40 T/t-Antigen Cancer Signature in Aggressive Human Breast, Prostate, and Lung Carcinomas with Poor Prognosis

Abstract

Understanding the genetic architecture of cancer pathways that distinguishes subsets of human cancer is critical to developing new therapies that better target tumors based on their molecular expression profiles. In this study, we identify an integrated gene signature from multiple transgenic models of epithelial cancers intrinsic to the functions of the Simian virus 40 T/t-antigens that is associated with the biological behavior and prognosis for several human epithelial tumors. This genetic signature, composed primarily of genes regulating cell replication, proliferation, DNA repair, and apoptosis, is not a general cancer signature. Rather, it is uniquely activated primarily in tumors with aberrant p53, Rb, or BRCA1 expression but not in tumors initiated through the overexpression of myc, ras, her2/neu, or polyoma middle T oncogenes. Importantly, human breast, lung, and prostate tumors expressing this set of genes represent subsets of tumors with the most aggressive phenotype and with poor prognosis. The T/t-antigen signature is highly predictive of human breast cancer prognosis. Because this class of epithelial tumors is generally intractable to currently existing standard therapies, this genetic signature identifies potential targets for novel therapies directed against these lethal forms of cancer. Because these genetic targets have been discovered using mammary, prostate, and lung T/t-antigen mouse cancer models, these models are rationale candidates for use in preclinical testing of therapies focused on these biologically important targets. [Cancer Res 2007;67(17):8065-80]

The DNA repair proteins BRCA1 and ERCC1 as predictive markers in sporadic ovarian cancer

“…The targeted expression of the SV40 T/t-antigen led to the discovery of a conserved gene transcriptional signature in multiple epithelial tumors. 52 This genetic signature was found to be activated uniquely in tumors with aberrant p53, Rb or BRCA1 expression, and in breast, prostate and lung cancer, associated with an aggressive phenotype and poor prognosis, suggesting that they may represent rationale candidates for the preclinical testing of biologically important targets.…”

Immunotherapy for SV40 T/t antigen-induced breast cancer by recombinant adeno-associated virus serotype 2 carrying interleukin-15 in mice

“…SV40 T/t antigens have been shown to be related to the biological behavior and prognosis of breast cancer (1)(2)(3). In this study, we successfully established SV40 T/t antigen-induced breast cancer transgenic mice.…”

“…Although breast cancer is complex and highly variable in its clinical course, studies have indicated that SV40 T/t antigens are related to the biological behavior and prognosis of breast cancer (1)(2)(3). Previous studies have indicated that interleukins (IL1, IL2, IL12, IL15, IL18, IL24), tumor necrosis factor-α (TNF-α), and the interferon-γ (IFN-γ) can control the immune response and play an important role in breast cancer immunotherapy (4)(5)(6).…”

Coordinated Activation of the Origin Licensing Factor CDC6 and CDK2 in Resting Human Fibroblasts Expressing SV40 Small T Antigen and Cyclin E

“…Thus, contrary to what is seen in normal murine cells (13), CDK2 activity appears essential for cell cycle progression when it is oncogenically driven by cyclin E and st expression (12). Because st is known to target pathways uniquely required for the transformation of human cells (14,15), tumor cells with altered pathways that mimic st/cyclin E expression could predictably be sensitive to selective inhibition of CDK2 activity.…”