This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jankiewicz, M. Articles by Desrivières, S. Search for Related Content PubMed PubMed Citation Articles by Jankiewicz, M. Articles by Desrivières, S. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Compound via MeSH Substance via MeSH

Mammalian Target of Rapamycin Regulates the Growth of Mammary Epithelial Cells through the Inhibitor of Deoxyribonucleic Acid Binding Id1 and Their Functional Differentiation through Id2

Georg Speyer Haus, Institute for Biomedical Research, D-60596 Frankfurt am Main, Germany

Address all correspondence and requests for reprints to: Sylvane Desrivières, Georg Speyer Haus, Institute for Biomedical Research, Paul-Ehrlich-Strasse 42-44, D-60596 Frankfurt am Main, Germany. E-mail: Desrivieres{at}em.uni-frankfurt.de.

Organ development requires the integration of multiple extracellular signals to assure a proper balance between proliferation and differentiation and to achieve and maintain specialized functions. Considerable progress has been made in the study of hormones and growth factors and in the understanding of the regulated intracellular pathways and transcriptional events that contribute to mammogenesis. Cell culture experiments have pointed out crucial pathways and components, which were subsequently validated in vivo experiments. We found that the mammalian target of rapamycin (mTOR) pathway is essential for both growth and differentiation of mammary epithelial cells and that the action of mTOR is mediated through the induction of the helix-loop-helix transcriptional regulators Id1 and Id2. Pharmacological inhibition of mTOR activity in HC11 mammary epithelial cells reduced cellular proliferation and prevented the lactogenic hormone-induced expression of milk proteins. Treatment of female mice with rapamycin impaired mammary gland differentiation and milk protein synthesis. The effects of mTOR on proliferation and differentiation require the functions of the helix-loop-helix proteins Id1 and Id2. Rapamycin treatment of HC11 cells resulted in a suppression of Id1 expression and an inhibition of proliferation. This effect of rapamycin was reversed by the forced expression of Id1. Rapamycin also prevented the induction of Id2 by lactogenic hormones and milk protein gene expression. Expression of a Id2 transgene bypassed the requirement of mTOR activity for ß-casein induction. These data suggest that mTOR activity has distinguishable functions in the proliferative and the differentiated state of mammary epithelial cells: it is a prerequisite for proliferation through the induction of Id1 and for differentiation-specific gene expression through the induction of Id2. The relative strengths of these proliferation and differentiation signals reflected by the expression levels of the individual Id proteins are crucial to the functional life cycle of mammary epithelial cells and might be disturbed in tumorigenesis.

This article has been cited by other articles:

				M. Veerasamy, T. Q. Nguyen, R. Motazed, A. L. Pearson, R. Goldschmeding, and M. E. C. Dockrell Differential regulation of E-cadherin and {alpha}-smooth muscle actin by BMP 7 in human renal proximal tubule epithelial cells and its implication in renal fibrosis Am J Physiol Renal Physiol, November 1, 2009; 297(5): F1238 - F1248. [Abstract] [Full Text] [PDF]

				C. R. Geest, F. J. Zwartkruis, E. Vellenga, P. J. Coffer, and M. Buitenhuis Mammalian target of rapamycin activity is required for expansion of CD34+ hematopoietic progenitor cells Haematologica, July 1, 2009; 94(7): 901 - 910. [Abstract] [Full Text] [PDF]

				Y. Feuermann, A. Shamay, and S. J. Mabjeesh Leptin Up-Regulates the Lactogenic Effect of Prolactin in the Bovine Mammary Gland In Vitro J Dairy Sci, November 1, 2008; 91(11): 4183 - 4189. [Abstract] [Full Text] [PDF]

				C. E. Caldon, A. Swarbrick, C. S.L. Lee, R. L. Sutherland, and E. A. Musgrove The Helix-Loop-Helix Protein Id1 Requires Cyclin D1 to Promote the Proliferation of Mammary Epithelial Cell Acini Cancer Res., April 15, 2008; 68(8): 3026 - 3036. [Abstract] [Full Text] [PDF]

				J. D. Mosley, J. T. Poirier, D. D. Seachrist, M. D. Landis, and R. A. Keri Rapamycin inhibits multiple stages of c-Neu/ErbB2 induced tumor progression in a transgenic mouse model of HER2-positive breast cancer Mol. Cancer Ther., August 1, 2007; 6(8): 2188 - 2197. [Abstract] [Full Text] [PDF]

				B. Linggi and G. Carpenter ErbB-4 s80 Intracellular Domain Abrogates ETO2-dependent Transcriptional Repression J. Biol. Chem., September 1, 2006; 281(35): 25373 - 25380. [Abstract] [Full Text] [PDF]