Overactive Transcription Factor Transforms Normal Epithelial Cells into Tumors

The Sp2 transcription factor, which is overexpressed in many types of human cancer, has been definitively linked to the transformation of epithelial cells into cancer cells in a transgenic mouse model.

Sp proteins are evolutionarily conserved transcription factors required for the expression of a wide variety of genes that are critical for development and cell-cycle progression. Deregulated expression of certain Sp proteins has been shown to be associated with the formation of a variety of human tumors. However, direct evidence linking a specific Sp protein to development of cancer has been lacking.

In the current study, investigators at North Carolina State University (Raleigh, NC, USA) worked with a transgenic mouse model in which animals were either hemizygous or homozygous for the Sp2 gene.

The investigators reported in the November 1, 2010, issue of the journal Cancer Research that overexpression of Sp2 in epidermal basal keratinocytes caused these cells to stop producing differentiated cells and instead to reproduce as undifferentiated (stem cells) cells that eventually progressed to a tumor. Transgenic animals that were homozygous rather than hemizygous for the Sp2 transgene exhibited a striking arrest in the epidermal differentiation program, perishing within two weeks of birth.

"Something happens to normal stem cells that changes the way SP2 is regulated, and it starts being overproduced,” said senior author Dr. Jon Horowitz, associate professor of molecular biomedical sciences at North Carolina State University. "SP2 basically hijacks the stem cell, and turns it into its evil twin – a cancer cell. Our hope is that we can find an "antidote” to SP2, to restore normal cell proliferation to those cancer stem cells and reverse the process.”

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