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Molecular and Cellular Biology, February 2007, p. 1442-1454, Vol. 27, No. 4
0270-7306/07/$08.00+0     doi:10.1128/MCB.01298-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

RANK Overexpression in Transgenic Mice with Mouse Mammary Tumor Virus Promoter-Controlled RANK Increases Proliferation and Impairs Alveolar Differentiation in the Mammary Epithelia and Disrupts Lumen Formation in Cultured Epithelial Acini{triangledown} ,{dagger}

Eva Gonzalez-Suarez,1* Daniel Branstetter,2 Allison Armstrong,1 Huyen Dinh,3 Hal Blumberg,3 and William C. Dougall1

Departments of Cancer Biology,1 Pathology,2 Inflammation, Amgen, Inc., 1201 Amgen Court West, Seattle, Washington 981193

Received 14 July 2006/ Returned for modification 5 September 2006/ Accepted 27 November 2006

RANK and RANKL, the key regulators of osteoclast differentiation and activation, also play an important role in the control of proliferation and differentiation of mammary epithelial cells during pregnancy. Here, we show that RANK protein expression is strictly regulated in a spatial and temporal manner during mammary gland development. RANK overexpression under the control of the mouse mammary tumor virus (MMTV) promoter in a transgenic mouse model results in increased mammary epithelial cell proliferation during pregnancy, impaired differentiation of lobulo-alveolar structures, decreased expression of the milk proteins ß-casein and whey acidic protein, and deficient lactation. We also show that treatment of three-dimensional in vitro cultures of primary mammary cells from MMTV-RANK mice with RANKL results in increased proliferation and decreased apoptosis in the luminal area, resulting in bigger acini with filled lumens. Taken together, these results suggest that signaling through RANK not only promotes proliferation but also inhibits the terminal differentiation of mammary epithelial cells. Moreover, the increased proliferation and survival observed in a three-dimensional culture system suggests a role for aberrant RANK signaling during breast tumorigenesis.

* Corresponding author. Mailing address: Department of Cancer Biology, AW2/D2262, Amgen Inc., 1201 Amgen Court West, Seattle, WA 98119. Phone: (206) 265-7148. Fax: (206) 217-0493. E-mail: gonzalee{at}amgen.com.

{triangledown} Published ahead of print on 4 December 2006.

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

Molecular and Cellular Biology, February 2007, p. 1442-1454, Vol. 27, No. 4
0270-7306/07/$08.00+0     doi:10.1128/MCB.01298-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Haslam, S. Z., Drolet, A., Smith, K., Tan, M., Aupperlee, M. (2008). Progestin-Regulated Luminal Cell and Myoepithelial Cell-Specific Responses in Mammary Organoid Culture. Endocrinology 149: 2098-2107 [Abstract] [Full Text]  


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