The Role of AP-1 and Other Transcription Factors in Cancer Cause and Prevention

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The AP-1 transcription factor is a heterodimer of Jun and Fos family proteins that binds to a specific sequence on the transcriptional promoter of certain genes and drives their transcription. Although basal AP-1 activity is needed for normal function, elevated AP-1 activity drives tumor progression in several human cancer sites. Keratinocyte-specific expression of Dominant Negative Jun in transgenic mice inhibits induced AP-1 and tumorigenesis without inhibiting cell proliferation or cell survival in multiple mouse models relevant to human carcinogenesis (Young et al., PNAS, 1999). Among these are mice whose skin tumor promotion response is elevated by expression of Human Papilloma Virus E7 (Young et al Molec Carc 2002) and mice induced to form squamous carcinomas by repeated exposure to UVB (Cooper et al Molec Cancer Res 2003). Tetracycline regulated expression of TAM 67 has been directed to mammary epithelia in collaboration with Powel Brown (Shen et al Dev Biol 2006) and has recently been tested for efficacy in preventing HER2/Neu induced mammary carcinogenesis. The results show substantial inhibition by the AP-1 blocker of preneoplastic as well as early and later stage tumor development (Shen et al Ca Prev Res 2008). Importantly, TAM67 expression was silenced in mammary tumors that developed. Inducible TAM67 has been found also to inhibit chemically induced lung carcinogenesis in collaboration with the laboratory of Jay Tichelaar (Cancer Prev Research 2010). The transcription factor NFkappa B is coordinately regulated with AP-1, suggesting the possible importance of both factors in transformation (Li et, Cancer Res 1997). Recent observations have identified NFkB non-responsiveness as an explanation for transformation non-responsiveness in the JB6 model (Hsu et al, Cancer Res 2001, Hu et al Carcinogenesis 2004). Transformation resistant cells owe their nonresponsiveness to an inability to activate NFkappa B p65 protein. p65 phosphorylation at S536 is important for DNA binding and for ubiquitination and degradation of inhibitor IkappaB alpha (Hu et al Molec Carcinog 2005). The observation that targeting AP-1 and NFkB elevation prevents tumor promotion and progression has been extended from the mouse JB6 model to mouse and human keratinocyte progression models, and to transgenic mouse models. Transgenic mice expressing AP-1/ NFkB inhibitor TAM 67 present a valuable opportunity to identify AP-1 or NFkB target genes whose expression is critical to neoplastic transformation. Expression microarray analysis has revealed TAM67 target genes that are being queried for functional significance in driving carcinogenesis. Such target genes may be promising new molecular targets for cancer prevention (Young et al Trends in Molec Medicine 2003). Recent studies have established the importance of chromatin architectural protein HMGA1 (Dhar et al Oncogene 2004), COX-2, osteopontin, urokinase plasminogen activator, Cxcl1 and MMP-10 (Matthews et al Cancer Res 2007) as functionally significant TAM67 targets. One of the recently discovered TAM67/AP-1 target genes is sulfiredoxin, a redox enzyme that is functionally significant both in tumor promotion and invasion as well as elevated in human cancer (Wei Q, et al, PNAS 2008 and PNAS 2011, Carcinogenesis 2013). The most recently discovered target of the AP-1 blocker is Wnt5a which signals through a non-canonical pathway involving protein kinase C and STAT3 to drive oncogenesis in several models (Kang et al Genes and Cancer, 2012). A drug discovery project in collaboration with the Molecular Targets Laboratory has identified compounds that mimic the specificity of TAM67, i.e. that inhibit AP-1 and/or NFkB and prevent carcinogenesis without inhibiting cell proliferation or cell survival. The primary AP-1 high throughput screen of 300,000 synthetic and natural products coupled to a cell proliferation (XTT) assay yielded a small set of AP-1 hits(Ruocco et al J Biomolec Screening 2007). The secondary assay has assessed inhibition of NFkB and identified an AP-1 inhibitor that is even more active against NFkappa B (Kang et al Mol Ca Ther, 2009). The new Chemical Biology Laboratory, CCR is generating analogs of this NFkappaB inhibitor and collaborating with Cristina Annunziata (MOB, CCR), winner of a Directors Innovation Award to assess its possible effectivenss against human ovarian cancer. In summary, recent accomplishments for this Project include 1) the discovery of new AP-1 regulated genes whose attenuation is responsible for the carcingenesis suppressing activity of AP-1 blocker TAM67, notably Sulfiredoxin and Wnt5a, and 2) the discovery of new small molecules that target AP-1 or NFkappaB without inhibiting cell viability.