Abstract 241: Transcription factor RBP-J-mediated signaling regulates basal cell carcinoma growth

Abstract Hair follicles (HF) and basal cell carcinomas (BCCs) can be regarded as ordered and disordered skin appendages respectively. They may utilize similar molecular mechanisms of growth. We examined the similarities and differences in gene expression between BCCs and HFs to define common and unique signaling pathways that distinguish an ordered skin appendage from a disordered skin growth. Nodular BCCs, non-follicular skin epithelium, and HF between the sebaceous gland and bulb region were microdissected and examined using microarrays. Selected genes were validated using quantitative PCR, immunohistochemistry and in vitro studies. Two differentially expressed gene sets were identified by significance analysis of microarray (SAM) in BCC and HF versus skin epithelium respectively. Subsequently, multiple signaling pathway analyses were conducted. The results indicated that Notch and Hedgehog signaling pathways were active in the growth of both HF and BCCs. However, Notch signaling, including tumor suppressor genes NOTCH1, NOTCH2, ligands JAG1, JAG2, signaling inhibitor NUMB, and downstream Notch pathway genes DTX1, DTX2, RBP-J, LFNG, HR, and HES7, all showed significant differential expression in BCCs compared to HF. The data suggests downstream gene expression in the Notch signaling pathway is suppressed in BCCs. We tested the effect of transcription factor RBP-J and found transcription factor RBP-J-mediated signaling suppresses BCC cell growth and induces cell apoptosis in vitro. Our data suggest that RBP-J serves as a tumor suppressor in BCC and BCCs deficient in RBP-J lose tumor repression activity. Modulation of the Notch pathway may be a focus for the development of BCC treatments. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 241. doi:10.1158/1538-7445.AM2011-241</jats:p

Superficial, Nodular, and Morpheiform Basal-Cell Carcinomas Exhibit Distinct Gene Expression Profiles

Basal-cell carcinoma (BCC), the most common neoplasm in humans, occurs in a variety of morphological presentations. The mechanisms of BCC development downstream of the initial genetic mutations are not well understood, and different BCC morphological presentations might exhibit distinct gene expression patterns. We investigated superficial (n=8), nodular (n=8), and morpheiform (n=7) BCCs using 21K cDNA microarrays. Global gene expression profiles between respective BCC subtypes, and as compared with normal skin (n=8), were statistically defined by significance analysis of microarrays (SAM). Thirty-seven genes were subsequently validated by quantitative reverse transcriptase-PCR analysis using an expanded set of 31 BCCs. Gene ontology analysis indicated that gene expression patterns of BCC subtypes in multiple biological processes showed significant variation, particularly in genes associated with the mitogen-activated protein kinase (MAPK) pathway. Notably, genes involved in response to DNA-damage stimulus were uniquely upregulated in morpheiform BCCs. Our results indicate a relative similarity in gene expression between nodular and superficial BCC subtypes. In contrast, morpheiform BCCs are more diverse, with gene expression patterns consistent with their more “invasive” phenotype. These data may help us understand the complex behavior of BCC subtypes and may eventually lead to new therapeutic strategies