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Development of Mammary Tumors by Conditional Expression of GLI1

¹ Center for Biosciences, Department of Biosciences and Nutrition and ² Unit for Morphological Phenotype Analysis, Clinical Research Center, and Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Huddinge, Sweden

Requests for reprints: Rune Toftgård, Department of Biosciences and Nutrition, Karolinska Institutet, Novum, SE-141 57 Huddinge, Sweden. Phone: 46-8-6081952; Fax: 46-8-6081501; E-mail: rune.toftgard{at}ki.se.

Key Words: Hedgehog • GLI1 • transgene • progenitor cells • mammary tumors

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. [Cancer Res 2009;69(11):4810–7]