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Molecular and Cellular Biology, September 2004, p. 8184-8194, Vol. 24, No. 18
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.18.8184-8194.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Role of F-Box Protein ßTrcp1 in Mammary Gland Development and Tumorigenesis

Yasusei Kudo ,^1,, Daniele Guardavaccaro,^1, Patricia G. Santamaria,¹ Ryo Koyama-Nasu,¹ Esther Latres,^1, Roderick Bronson,² Lili Yamasaki,³ and Michele Pagano^1*

Department of Pathology and NYU Cancer Institute, New York University School of Medicine,¹ Biological Sciences, Columbia University, New York, New York,³ Tufts University School of Veterinary Medicine, North Grafton, Massachusetts²

Received 22 April 2004/ Returned for modification 27 May 2004/ Accepted 23 June 2004

The F-box protein ßTrcp1 controls the stability of several crucial regulators of proliferation and apoptosis, including certain inhibitors of the NF-B family of transcription factors. Here we show that mammary glands of ßTrcp1^–/– female mice display a hypoplastic phenotype, whereas no effects on cell proliferation are observed in other somatic cells. To investigate further the role of ßTrcp1 in mammary gland development, we generated transgenic mice expressing human ßTrcp1 targeted to epithelial cells under the control of the mouse mammary tumor virus (MMTV) long terminal repeat promoter. Compared to controls, MMTV ßTrcp1 mammary glands display an increase in lateral ductal branching and extensive arrays of alveolus-like protuberances. The mammary epithelia of MMTV ßTrcp1 mice proliferate more and show increased NF-B DNA binding activity and higher levels of nuclear NF-B p65/RelA. In addition, 38% of transgenic mice develop tumors, including mammary, ovarian, and uterine carcinomas. The targeting of ßTrcp1 to lymphoid organs produces no effects on these tissues. In summary, our results support the notion that ßTrcp1 positively controls the proliferation of breast epithelium and indicate that alteration of ßTrcp1 function and expression may contribute to malignant behavior of breast tumors, at least in part through NF-B transactivation.

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* Corresponding author. Mailing address: Department of Pathology, MSB 599, NYU School of Medicine, 550 First Ave., New York, NY 10016. Phone: (212) 263-5332. Fax: (212) 263-5107. E-mail: michele.pagano{at}med.nyu.edu.

Y.K. and D.G. contributed equally to this work.

Present address: Department of Oral Maxillofacial Pathobiology, Division of Frontier Medical Science, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.

Present address: Regeneron Pharmaceuticals, Tarrytown, N.Y.

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Molecular and Cellular Biology, September 2004, p. 8184-8194, Vol. 24, No. 18
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.18.8184-8194.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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