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Protein 4.1B expression is induced in mammary epithelial cells during pregnancy and regulates their proliferation

Oncogene volume 24, pages 6502–6515 (2005)Cite this article

Abstract

4.1B is a member of the protein 4.1 superfamily of proteins that link transmembrane proteins to the actin cytoskeleton. The 4.1B gene localizes to chromosome 18p11.3, which undergoes loss of heterozygosity in mammary tumors. Here, we examine the expression of 4.1B in murine mammary epithelium and find that 4.1B is dramatically upregulated in mammary epithelial cells during pregnancy when there is extensive cell proliferation. In contrast, 4.1B is not expressed in virgin, lactating, or involuting mammary epithelium. To examine the consequence of 4.1B loss on mammary epithelial cell proliferation, we analysed mammary glands in 4.1B-null mice. 4.1B loss results in a significant increase in mammary epithelial cell proliferation during pregnancy, but has no effect on mammary epithelial cell proliferation, in virgin or involuting mice. Furthermore, we show that 4.1B inhibits the proliferation of mammary epithelial cell lines by inducing a G1 cell cycle arrest, characterized by decreased cyclin A expression and reduced Rb phosphorylation, and accompanied by reduced erbB2 phosphorylation. This cell cycle arrest does not involve alterations in the activities of MAPK, JNK, or Akt. Collectively, our findings demonstrate that 4.1B regulates mammary epithelial cell proliferation during pregnancy and suggest that its loss may influence mammary carcinoma pathogenesis in multiparous women.

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Acknowledgements

We thank Sue Heffelfinger, Wallace Ip, and Nancy Ratner for helpful comments, Erik Knudsen, Eliot Spindel, and Mihael Iordanov for helpful comments and reagents. This work was supported in part by funding from the National Institutes of Health (NS39550 to LSS and NS41520 to DHG), a University of Cincinnati Distinguished Graduate Student Award (to RK), a Department of Defense grant (DAMD17-04-0266 to DHG), and an NIH grant supporting the Oregon National Primate Research Center (RR00163).

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Authors and Affiliations

  1. Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185th Ave., Beaverton, 97006, OR, USA

    Robin Kuns & Larry S Sherman

  2. Department of Cell Biology, Neurobiology & Anatomy, University of Cincinnati School of Medicine, Cincinnati, 45267, OH, USA

    Robin Kuns

  3. Molecular and Cellular Oncogenomics Program, The Wistar Institute, 19104, Philadelphia, PA, USA

    Joseph L Kissil

  4. Department of Neurosurgery, David and Doreen Hermelin Laboratory of Molecular Oncogenetics, Hermelin Brain Tumor Center, Henry Ford Hospital, 48202, Detroit, MI, USA

    Irene F Newsham

  5. Department of Biology and Center for Cancer Research, and Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, 02139, MA, USA

    Tyler Jacks

  6. Department of Neurology, Washington University School of Medicine, St Louis, 63110, MO, USA

    David H Gutmann

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Correspondence to Larry S Sherman.

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Kuns, R., Kissil, J., Newsham, I. et al. Protein 4.1B expression is induced in mammary epithelial cells during pregnancy and regulates their proliferation. Oncogene 24, 6502–6515 (2005). https://doi.org/10.1038/sj.onc.1208813

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