Abstract C4: Sp2: A regulator of stem cell differentiation and tumorigenesis

Abstract

Abstract Transcription factors regulate gene expression and de-regulation of their activities can transform normal cells into tumor cells. The Sp-family of transcription factors consists of nine distinct proteins (Sp1-9) that are evolutionarily-conserved and share a common DNA-binding domain. Sp2 is one of several poorly-characterized members of this transcription factor family. Previous data from our lab and others has indicated that Sp2 is over-expressed in human prostate cancer and in murine skin squamous cell carcinoma. To determine if the de-regulated expression of Sp2 is oncogenic, transgenic mice over-expressing mouse Sp2 via the keratin 5 (K5) promoter were generated. This promoter drives expression of linked genes in basal cells of stratified epithelia, such as skin. Two different transgenic lines (Family A and C) were derived and characterized. The transgenes carried by Family A and C mice were localized to chromosomes 6 and 5, respectively. Endogenous genes were not disrupted by transgene integration in Family A, whereas transgene integration in Family C mice occurred within the latrophilin 3 (Lphn3/CIRL3) locus. Homozygous Family A and C animals develop normally and are indistinguishable from wild-type and hemizygous littermates until post-natal day 2. Family C animals invariably perish at this time due to skin deterioration whereas homozygous Family A animals develop skin lesions on post-natal day 4, are runted and developmentally retarded and perish prior to post-natal day 13. Immunohistochemical staining revealed that that an expanded population of K5-negative, K14-positive progenitor cells inundates all epidermal cell layers of homozygous Family A animals. Expression of markers of differentiated basal keratinocytes (e.g., keratin 10, loricrin) is decreased in homozygous Family A animals. The expression level of keratin 6, a marker of epidermal wounding, inflammation, and/or tumorigenesis is increased in Family A animals beginning at post-natal day 4 as is the expression and distribution of CD34, a hair follicle stem cell marker. Hemizygous Family A animals progress to adulthood unremarkably, however 70% exhibit varying degrees of alopecia (hair loss) beginning at 1 month of age. Family C hemizygotes do not develop alopecia, however an expanded pool of progenitor cells renders these animals susceptible to wound-induced neoplasia, and the incidence of papilloma formation rises with an age-dependent increase in Sp2 levels. Sp2 expression in Family A hemizygotes is insufficient to promote wound-induced neoplastic growth, but epidermal differentiation is slowed sufficiently to retard rates of wound healing. These and other results have led us to speculate that Sp2 functions to limit stem cell differentiation and thus its over-expression contributes to the outgrowth of poorly-differentiated, tumorigenic cells. Citation Information: Cancer Res 2009;69(23 Suppl):C4.