Background β-catenin functions in signal transduction in the Wnt signalling pathway, which has recently been implicated in hair follicle (HF) morphogenesis. β-catenin gene mutations affecting exon 3 have been reported in a high percentage of human pilomatrixomas. However, the expression pattern of β-catenin in human HFs and pilomatrixomas has not been reported.
Objectives To analyse immunohistochemically the expression pattern of β-catenin in normal anagen HFs and in 40 human pilomatrixomas.
Methods In 11 of these tumours we also studied exon 3 β-catenin gene mutations by polymerase chain reaction and direct sequencing. As these mutations have been related to a replication error (RER) phenotype in other tumour types, we explored whether or not this association also occurs in pilomatrixomas.
Results β-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 cortical cells, cortical and cuticular cells expressed β-catenin in the nucleus, suggesting a role in signal transduction. In addition, some fibroblasts of the dermal papilla also showed nuclear expression of β-catenin. All 40 analysed pilomatrixomas showed intense nuclear and cytoplasmic β-catenin expression in proliferating matrix (basaloid) cells. In areas of maturation, transitional cells mainly showed cytoplasmic and membranous expression of β-catenin, while only a few cells retained nuclear expression. Shadow or ghost cells did not show β-catenin expression. Three of 11 tumours (26%) had β-catenin mutations. All three had the same heterozygote mis-sense mutation: a G to T change affecting the first nucleotide at codon 32 (D32Y). None of the 11 tumours studied had a positive RER phenotype.
Conclusions Present and previous studies suggest that the Wnt/β-catenin/Tcf-Lef pathway is activated in normal matrix cells of the HF to induce differentiation to the hair shaft. Additionally, the β-catenin mutation in matrix cells of the HF stabilizes β-catenin protein, which translocates 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.