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J. Biol. Chem., Vol. 282, Issue 49, 36090-36101, December 7, 2007

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Targeted Expression of GLI1 in the Mammary Gland Disrupts Pregnancy-induced Maturation and Causes Lactation Failure^*

Marie Fiaschi, Björn Rozell, Åsa Bergström, Rune Toftgård¹, and Marika I. Kleman

From the Department of Bioscience and Nutrition and Unit for Morphological Phenotype Analysis, Clinical Research Center, and Department of Laboratory Medicine Division of Pathology, Karolinska Institutet, Novum, SE-141 57 Huddinge, Sweden

The Hedgehog signaling pathway regulates the development and function of numerous tissues and when mis-regulated causes tumorigenesis. To assess the role of a deregulated Hedgehog signaling pathway in the mammary gland we targeted the expression of the Hedgehog effector protein, GLI1, to mammary epithelial cells using a bigenic inducible system. A constitutively active Hedgehog signaling pathway resulted with 100% penetrance in an undifferentiated mammary lobuloalveolar network during pregnancy. GLI1-expressing transgenic females were unable to lactate and milk protein gene expression was essentially absent. The inability to lactate was permanent and independent of continued GLI1 transgene expression. An increased expression of the GLI1 response gene Snail coupled to reduced expression of E-cadherin and STAT5 in the transgenic mammary gland provides a likely molecular explanation, underlying the observed phenotypic changes. In addition, remodeling of the mammary gland after parturition was impaired and expression of GLI1 was associated with accumulation of cellular debris in the mammary ducts during involution, indicating a defect in the clearance of dead cells. Areas with highly proliferative epithelial cells were observed in mammary glands with induced expression of GLI1. Within such areas an increased frequency of cells expressing nuclear Cyclin D1 was observed. Taken together the data support the notion that correct regulation of Hedgehog signaling within the epithelial cell compartment is critical for pregnancy-induced mammary gland development and remodeling.

Received for publication, May 24, 2007 , and in revised form, October 9, 2007.

^* The work was supported by the Swedish Cancer Society, National Institutes of Health Program Project Grant AR47898 and NCI MMHCC Grant U01 CA105491. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 4686081952; Fax: 4686081501; E-mail: rune.toftgard{at}biosci.ki.se.

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