QUICK SEARCH:   [advanced] Author: Keyword(s):
Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents

First published online 7 February 2007
doi: 10.1242/dev.02797

This Article Figures Only Full Text Full Text (PDF) Supplementary Material All Versions of this Article: dev.02797v1 134/6/1231    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Related articles in Development Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Moraes, R. C. Articles by Lewis, M. T. Search for Related Content PubMed PubMed Citation Articles by Moraes, R. C. Articles by Lewis, M. T. Social Bookmarking                         What's this?

Constitutive activation of smoothened (SMO) in mammary glands of transgenic mice leads to increased proliferation, altered differentiation and ductal dysplasia

Baylor Breast Center and Department of Molecular and Cellular Biology, Room N1210; MS:BCM600, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.

^* Author for correspondence (e-mail: mtlewis{at}breastcenter.tmc.edu)

Accepted 3 January 2007

The hedgehog signaling network regulates pattern formation, proliferation, cell fate and stem/progenitor cell self-renewal in many organs. Altered hedgehog signaling is implicated in 20-25% of all cancers, including breast cancer. We demonstrated previously that heterozygous disruption of the gene encoding the patched-1 (PTCH1) hedgehog receptor, a negative regulator of smoothened (Smo) in the absence of ligand, led to mammary ductal dysplasia in virgin mice. We now show that expression of activated human SMO (SmoM2) under the mouse mammary tumor virus (MMTV) promoter in transgenic mice leads to increased proliferation, altered differentiation, and ductal dysplasias distinct from those caused by Ptch1 heterozygosity. SMO activation also increased the mammosphere-forming efficiency of primary mammary epithelial cells. However, limiting-dilution transplantation showed a decrease in the frequency of regenerative stem cells in MMTV-SmoM2 epithelium relative to wild type, suggesting enhanced mammosphere-forming efficiency was due to increased survival or activity of division-competent cell types under anchorage-independent growth conditions, rather than an increase in the proportion of regenerative stem cells per se. In human clinical samples, altered hedgehog signaling occurs early in breast cancer development, with PTCH1 expression reduced in 50% of ductal carcinoma in situ (DCIS) and invasive breast cancers (IBC). Conversely, SMO is ectopically expressed in 70% of DCIS and 30% of IBC. Surprisingly, in both human tumors and MMTV-SmoM2 mice, SMO rarely colocalized with the Ki67 proliferation marker. Our data suggest that altered hedgehog signaling may contribute to breast cancer development by stimulating proliferation, and by increasing the pool of division-competent cells capable of anchorage-independent growth.

Key words: Hedgehog signaling, Stem cell, Progenitor cell, Invasive breast cancer, Ductal carcinoma in situ

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?

Related articles in Development:

Mammary development: from normal to pathological

Development 2007 134: e604. [Full Text]  

This article has been cited by other articles:

				J. E. Visvader Keeping abreast of the mammary epithelial hierarchy and breast tumorigenesis Genes & Dev., November 15, 2009; 23(22): 2563 - 2577. [Abstract] [Full Text] [PDF]

				B. Gu, P. Sun, Y. Yuan, R. C. Moraes, A. Li, A. Teng, A. Agrawal, C. Rheaume, V. Bilanchone, J. M. Veltmaat, et al. Pygo2 expands mammary progenitor cells by facilitating histone H3 K4 methylation J. Cell Biol., June 1, 2009; 185(5): 811 - 826. [Abstract] [Full Text] [PDF]

				M. Kasper, V. Jaks, M. Fiaschi, and R. Toftgard Hedgehog signalling in breast cancer Carcinogenesis, June 1, 2009; 30(6): 903 - 911. [Abstract] [Full Text] [PDF]

				M. Fiaschi, B. Rozell, A. Bergstrom, and R. Toftgard Development of Mammary Tumors by Conditional Expression of GLI1 Cancer Res., June 1, 2009; 69(11): 4810 - 4817. [Abstract] [Full Text] [PDF]

				R. C. Moraes, H. Chang, N. Harrington, J. D. Landua, J. T. Prigge, T. F. Lane, B. J. Wainwright, P. A. Hamel, and M. T. Lewis Ptch1 is required locally for mammary gland morphogenesis and systemically for ductal elongation Development, May 1, 2009; 136(9): 1423 - 1432. [Abstract] [Full Text] [PDF]

				M.-L. Asselin-Labat, F. Vaillant, M. Shackleton, T. Bouras, G.J. Lindeman, and J.E. Visvader Delineating the Epithelial Hierarchy in the Mouse Mammary Gland Cold Spring Harb Symp Quant Biol, November 19, 2008; (2008) sqb.2008.73.020v2. [Abstract] [PDF]

				L.-H. Gu and P. A. Coulombe Hedgehog Signaling, Keratin 6 Induction, and Sebaceous Gland Morphogenesis: Implications for Pachyonychia Congenita and Related Conditions Am. J. Pathol., September 1, 2008; 173(3): 752 - 761. [Abstract] [Full Text] [PDF]

				C. J. Watson and W. T. Khaled Mammary development in the embryo and adult: a journey of morphogenesis and commitment Development, March 15, 2008; 135(6): 995 - 1003. [Abstract] [Full Text] [PDF]

				M. Fiaschi, B. Rozell, A. Bergstrom, R. Toftgard, and M. I. Kleman Targeted Expression of GLI1 in the Mammary Gland Disrupts Pregnancy-induced Maturation and Causes Lactation Failure J. Biol. Chem., December 7, 2007; 282(49): 36090 - 36101. [Abstract] [Full Text] [PDF]