Basal cell carcinoma (BCC) is the most common non-melanomatous skin cancer, typically arising in sun-exposed areas such as the head and neck. Defective signaling through the Hedgehog (HH) signaling pathway forms the molecular basis for BCC. Surgery remains the mainstay of treatment. Basal cell carcinoma of the genital tract is rare as is metastatic BCC. We report a case of metastatic BCC in a young woman with previously resected vulval BCC presenting six years later with inguinal nodal recurrence and multiple lung metastases.

Overexpression of Akt drives the growth of sporadic and hereditary cancers in human populations. We have shown that this pathway is essential for Shh signaling and for the growth of murine BCCs. Inhibition of phosphatase and tensin homolog (PTEN) via mutation, deletion, or epigenetic silencing can augment Akt activation in various cancers; however, these drivers of PTEN inactivation rarely occur in human BCCs, and little is known about their role in murine BCCs. Here, we show that UV-induced BCCs, generated in our Ptch1 +/-/SKH-1 mouse model, as well as sporadic human BCCs manifest increased Akt1 phosphorylation. Detailed analysis of tissue and tumor sections from these sources showed that PTEN was undetectable in tumor tissue whereas it is highly expressed in tumor stroma suggesting a distinct mechanism of PTEN inactivation in BCC cells. We have been studying the role of Sox9, an SRY-related transcription factor known to have opposing modes of transcriptional regulation (i.e., activation and repression). SOX9 is downstream of Gli1 and is overexpressed in BCCs. We identified SOX9 binding motifs in the promoter region of PTEN. Using ASZ001 murine BCC cells transduced with a PTEN-luc reporter construct, we assessed PTEN promoter activity in the absence or presence of SOX9. Genetic ablation of SOX9 resulted in increased PTEN promoter activity whereas overexpression of SOX9 diminished PTEN mRNA levels in these cells. Furthermore, treatment of ASZ001 cells with the SMO inhibitor cyclopamine (0 e 20 mM) dose-dependently increased PTEN promoter activity and PTEN expression and attenuated Akt phosphorylation. These data demonstrate that SOX9 negatively regulates PTEN in ASZ001 cells and suggest that SOX9-mediated repression of PTEN contributes to aberrant Akt signaling in BCC pathogenesis.