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Molecular and Cellular Biology, July 2007, p. 5135-5146, Vol. 27, No. 14
0270-7306/07/$08.00+0     doi:10.1128/MCB.02282-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

c-Myc Transforms Human Mammary Epithelial Cells through Repression of the Wnt Inhibitors DKK1 and SFRP1{triangledown} ,{dagger}

Victoria H. Cowling,1 Celina M. D'Cruz,2 Lewis A. Chodosh,2 and Michael D. Cole1*

Departments of Pharmacology and Genetics, Dartmouth Medical School, Norris Cotton Cancer Center, One Medical Center Drive, Lebanon, New Hampshire 03756,1 Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19194-61602

Received 6 December 2006/ Returned for modification 8 March 2007/ Accepted 30 April 2007

c-myc is frequently amplified in breast cancer; however, the mechanism of myc-induced mammary epithelial cell transformation has not been defined. We show that c-Myc induces a profound morphological transformation in human mammary epithelial cells and anchorage-independent growth. c-Myc suppresses the Wnt inhibitors DKK1 and SFRP1, and derepression of DKK1 or SFRP1 reduces Myc-dependent transforming activity. Myc-dependent repression of DKK1 and SFRP1 is accompanied by Wnt target gene activation and endogenous T-cell factor activity. Myc-induced mouse mammary tumors have repressed SFRP1 and increased expression of Wnt target genes. DKK1 and SFRP1 inhibit the transformed phenotype of breast cancer cell lines, and DKK1 inhibits tumor formation. We propose a positive feedback loop for activation of the c-myc and Wnt pathways in breast cancer.

* Corresponding author. Mailing address: Dartmouth Medical School, Norris Cotton Cancer Center, One Medical Center Drive, Lebanon, NH 03756. Phone: (603) 653-9975. Fax: (603) 653-9952. E-mail: mcole{at}dartmouth.edu

{triangledown} Published ahead of print on 7 May 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, July 2007, p. 5135-5146, Vol. 27, No. 14
0270-7306/07/$08.00+0     doi:10.1128/MCB.02282-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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