A diverse set of cellular defects, presumably elicited by multiple genetic alterations, underlies
cancer development. Aberrant Hedgehog (Hh) signaling has recently been implicated in the development and maintenance of
breast cancer. However, evidence conclusively showing that activated Hh signaling can induce mammary
tumors is lacking. We now show that transgenic expression of the Hh effector
protein GLI1 under the regulation of the mouse mammary tumor virus promoter, expressed in the mouse mammary gland, is associated with the appearance of hyperplastic lesions, defective terminal end buds, and
tumor development. The GLI1-induced
tumors are histologically heterogeneous and involve the expansion of a population of epithelial cells expressing the progenitor cell markers
keratin 6 and Bmi-1. Moreover,
tumor cells express genes involved in proliferation, cell survival, and
metastasis. GLI1-induced
tumors do not fully regress following transgene deinduction, indicating that some
tumors develop and are maintained autonomously, independent of sustained transgenic GLI1 expression. The data strongly support a role of Hh/GLI signaling in
breast cancer development and suggest that inhibition of this signaling pathway represents a new therapeutic opportunity for limiting
tumorigenesis and early tumorigenic progression.