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Three-dimensional collagen represses cyclin E1 via β1 integrin in invasive breast cancer cells

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Abstract

The behavior of breast epithelial cells is influenced by their microenvironment which includes stromal cells and extracellular matrix (ECM). During cancer progression, the tissue microenvironment fails to control proliferation and differentiation, resulting in uncontrolled growth and invasion. Upon invasion, the ECM encountered by breast cancer cells changes from primarily laminin and collagen IV to primarily collagen I. We show here that culturing invasive breast cancer cells in 3-dimensional (3D) collagen I inhibits proliferation through direct regulation of cyclin E1, a G1/S regulator that is overexpressed in breast cancer. When the breast cancer cell line MDA-MB-231 was cultured within 3D collagen I gels, the G1/S transition was inhibited as compared to cells cultured on conventional 2D collagen or plastic dishes. Cells in 3D collagen downregulated cyclin E1 protein and mRNA, with no change in cyclin D1 level. Cyclin D1 was primarily cytoplasmic in 3D cultures, and this was accompanied by decreased phosphorylation of Rb, a nuclear target for both cyclin E1- and cyclin D1-associated kinases. Positive regulators of cyclin E1 expression, the transcription factor c-Myc and cold-inducible RNA binding protein (CIRP), were decreased in 3D collagen cultures, while the collagen I receptor β1 integrin was greatly increased. Inhibition of β1 integrin function rescued proliferation and cyclin E1 expression as well as c-Myc expression and Rb phosphorylation, but cyclin D1 remained cytoplasmic. We conclude that cyclin E1 is repressed independent of effects on cyclin D1 in a 3D collagen environment and dependent on β1 integrin interaction with collagen I, reducing proliferation of invasive breast cancer cells.

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Acknowledgments

This study was supported by the National Cancer Institute-National Institutes of Health R01 CA095898 to RSH. We thank Therese Mitchell and Tamara Howard for technical support. AIIB2 monoclonal antibody (Dr. Caroline H. Damsky) was obtained from the Developmental Studies Hybridoma Bank developed under the auspices of the NICHD and maintained by The University of Iowa, Department of Biology, Iowa City, IA 52242. Images were generated in the UNM Cancer Center Microscopy Facility, supported from NCRR 1 S10 RR14668, NSF MCB9982161, NCRR P20 RR11830, NCI P30 CA118100, NCRR S10 RR19287, NCRR S10 RR016918, the UNM HSC, and the UNM Cancer Center.

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Authors and Affiliations

  1. Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, MSC08 4750, 1 University of New Mexico, Albuquerque, NM, 87131-0001, USA

    Yuehan Wu, Xun Guo, Yekaterina Brandt, Helen J. Hathaway & Rebecca S. Hartley

  2. Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, NM, 87131, USA

    Yuehan Wu, Xun Guo, Yekaterina Brandt, Helen J. Hathaway & Rebecca S. Hartley

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  1. Yuehan Wu
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Correspondence to Rebecca S. Hartley.

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Wu, Y., Guo, X., Brandt, Y. et al. Three-dimensional collagen represses cyclin E1 via β1 integrin in invasive breast cancer cells. Breast Cancer Res Treat 127, 397–406 (2011). https://doi.org/10.1007/s10549-010-1013-x

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  • DOI: https://doi.org/10.1007/s10549-010-1013-x

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