Collective downregulation of a group of tumor suppressors in response to EGF: The role of TSHZ2 in cancer progression
Mary Luz Uribe Ríos
Centro de Investigación del Cáncer (CIC-IBMCC)
Unlike early transcriptional responses to growth factors, the late events are poorly understood. We report multiple transcripts persistently downregulated following stimulation of mammary cells with EGF. Commonly, the delayed downregulated genes (DDGs) are lowly expressed in mammary tumors, and higher expression predicts better prognosis. The products of several DDGs directly inactivate specific oncoproteins and qualify as tumor suppressors. Focusing on TSHZ2, we show that this transcription factor inhibits tumorigenesis in mice. Unexpectedly, TSHZ2 localizes to a locus amplified in breast cancer, but we found that targeted hypermethylation permits frequent downregulation in patients. In mice, Tshz2 accelerated mammary gland differentiation. Yeast 2-hybrid screens found that TSHZ2 binds to PRC1 and additional proteins involved in cytokinesis. Like p53, TSHZ2 transcriptionally downregulates PRC1. Recognizing DDGs as a distinct group uncovers a novel pool of tumor suppressors and sheds new light on roles played by growth factors in cancer progression.