beta-catenin expression in pilomatrixomas. Relationship with beta-catenin gene mutations and comparison with beta-catenin expression in normal hair follicles

Background beta -catenin functions in signal transduction in the Writ signa lling pathway, which has recently been implicated in hair follicle (HF) mor phogenesis. beta -catenin gene mutations affecting exon 3 have been reporte d in a high percentage of human pilomatrixomas. However, the expression pat tern of beta -catenin in human HFs and pilomatrixomas has not been reported . Objectives To analyse immunohistochemically the expression pattern of beta -catenin in normal anagen HFs and in 40 human pilomatrixomas. Methods In 11 of these tumours we also studied exon 3 beta -catenin gene mu tations by polymerase chain reaction and direct sequencing. As these mutati ons have been related to a replication error (RER) phenotype in other tumou r types, we explored whether or not this association also occurs in pilomat rixomas. Results beta -catenin was expressed in the cell membranes of the outer and inner root sheaths and in matrix cells located at the base and periphery of the HF bulb. However, central matrix cells that differentiate into cortica l cells, cortical and cuticular cells expressed beta -catenin in the nucleu s, suggesting a role in signal transduction. In addition, some fibroblasts of the dermal papilla also showed nuclear expression of (beta -catenin. All 40 analysed pilomatrixomas showed intense nuclear and cytoplasmic beta -ca tenin expression in proliferating matrix (basaloid) cells. In areas of matu ration, transitional cells mainly showed cytoplasmic and membranous express ion of beta -catenin. while only a few cells retained nuclear expression. S hadow or ghost cells did not show beta -catenin expression. Three of 11 tum ours (26%) had beta -catenin mutations. All three had the same heterozygote mis-sense mutation: a G to T change affecting the first nucleotide at codo n 32 (D32Y). None of the 11 tumours studied had a positive RER phenotype. Conclusions Present and previous studies suggest that the Wnt/beta -catenin /Tcf-Lef pathway is activated in normal matrix cells of the HF to induce di fferentiation to the hair shaft. Additionally, the beta -catenin mutation i n matrix cells of the HF stabilizes beta -catenin protein, which translocat es into the nucleus, where it activates of gene transcription together with lymphoid enhancer factor-1 producing pilomatrixoma. These mutations occur without an underlying defect in DNA mismatch repair.