Basal Cell Carcinoma and Aberrant Hedgehog Signaling

Forkhead Box Transcription Factors & BCC

Although the role of deregulated Hh signaling in BCC is very well delineated, and a definite role for Wnt is beginning to emerge, there is however only limited knowledge so far of which Hh/Wnt downstream events are required for BCC tumorigenesis.

The forkhead box (FOX) transcription factor genes have been implicated in both embryonic development and adult tissue homeostasis by regulating cell growth, proliferation, differentiation, longevity and transformation.^[89] A number of murine Fox genes, such as Foxa2, Foxd2 andFoxf1 have been demonstrated to be expressed within areas of active Hh signaling during embryonic development,^[90–92] and therefore they appear to be direct targets of Hh signaling. The FOXM1 member is expressed ubiquitously in all proliferating mammalian cells and cancer cell lines,^[93–97] has been demonstrated to play important roles in regulating the expression of genes that are involved in cell proliferation, differentiation, and transformation by promoting both G1/S and G2/M transition, and is highly expressed in several human cancers.^[98–104]FoxM1 expression is associated with progressive pathologic features and an aggressive clinical course in lung and cervical cancer as well as in glioma cases.^{[103,105,106]} Teh and collaborators investigated the expression of this gene family in normal human skin, primary cultured human keratinocytes, and BCC and SCC samples, and found that FOXM1 is specifically upregulated in BCCs but not in normal skin, cultured keratinocytes or SCCs. Expression of Gli1 in primary keratinocytes and other cell lines caused a significant elevation of FOXM1 mRNA level and transcriptional activity, indicating that FOXM1 is a downstream target of Gli1.^[100]

Two reports have added insights into the role of FOX genes in BCC tumorigenesis. Eichberger and colleagues established that FOXE1, another member of the FOX family, is expressed in basal keratinocytes and in the ORS of hair follicles in human epidermis, as well as in human BCC.^[107] Brancaccio and colleagues demonstrated that murine Foxe1 is required in hair follicle morphogenesis and that in Foxe1-null, skin hair follicle downgrowth is disrupted, with disorientation, misalignement and aberrant shape of follicles.^[108] BCC has classically been considered a follicular tumor,^[109] and the above findings reinforce the hypothesis that Foxe1 is a downstream target of Shh in hair follicle morphogenesis as well as in BCC.

Thus, at least some of the FOX genes may represent important players in the expression changes downstream of Hh signaling that are required for BCC tumorigenesis.

Cite this: Basal Cell Carcinoma and the Carcinogenic Role of Aberrant Hedgehog Signaling - Medscape - Jun 01, 2010.

Table 1. Frequencies of sporadic basal cell carcinoma-carrying mutations in hedgehog signaling molecules.
Gene^†	Mutations (%)	Ref.
Ptch1	12/36 (33.3)	^[19]
Ptch1	3/26 (11.5)	^[34]
Ptch1	29/60 (48.3)	^[35]
Ptch1	6/15 (40)	^[110]
Ptch1	3/9 (33.3)	^[33]
Ptch1 Smo	8/31 (25.8) 4/31 (13)	^[39]
Ptch1 Smo Sufu	28/42 (66.7) 4/42 (9.5) 2/42 (4.8)	^[40]
Smo	3/47 (6.4)	^[37]
Smo	20/97 (20.6)	^[38]

^†The majority of mutations were found in different exons of the genes analyzed.

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