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LRIG1 opposes epithelial-to-mesenchymal transition and inhibits invasion of basal-like breast cancer cells

Oncogene volume 35, pages 2932–2947 (2016)Cite this article

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Abstract

LRIG1 (leucine-rich repeat and immunoglobulin-like domain containing), a member of the LRIG family of transmembrane leucine-rich repeat-containing proteins, is a negative regulator of receptor tyrosine kinase signaling and a tumor suppressor. LRIG1 expression is broadly decreased in human cancer and in breast cancer and low expression of LRIG1 has been linked to decreased relapse-free survival. Recently, low expression of LRIG1 was revealed to be an independent risk factor for breast cancer metastasis and death. These findings suggest that LRIG1 may oppose breast cancer cell motility and invasion, cellular processes that are fundamental to metastasis. However, very little is known of LRIG1 function in this regard. In this study, we demonstrate that LRIG1 is downregulated during epithelial-to-mesenchymal transition (EMT) of human mammary epithelial cells, suggesting that LRIG1 expression may represent a barrier to EMT. Indeed, depletion of endogenous LRIG1 in human mammary epithelial cells expands the stem cell population, augments mammosphere formation and accelerates EMT. Conversely, expression of LRIG1 in highly invasive Basal B breast cancer cells provokes a mesenchymal-to-epithelial transition accompanied by a dramatic suppression of tumorsphere formation and a striking loss of invasive growth in three-dimensional culture. LRIG1 expression perturbs multiple signaling pathways and represses markers and effectors of the mesenchymal state. Furthermore, LRIG1 expression in MDA-MB-231 breast cancer cells significantly slows their growth as tumors, providing the first in vivo evidence that LRIG1 functions as a growth suppressor in breast cancer.

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Acknowledgements

We thank Dr Robert Weinberg (Whitehead Institute) for the kind gift of the HMLE and HMLE-Twist-ER cells, Dr Paola Marignani (Dalhousie University) for the kind gift of the 293GPG packaging cell line, and Dr Ashley Hodel and Mr Sina Azadi for technical support and advice. Dr Nucharee Yokdang was a trainee on the T32 training grant in Oncogenic Signals and Chromosome Biology (CA108459). Dr Joseph Tellez was supported by a Lawrence Livermore National Labs UC Davis Fitzpatrick Research Fellowship. This work was supported by NIH grants CA118384 (Sweeney) and CA166412 (Carraway). We acknowledge the UC Davis Comprehensive Cancer Center Support Grant (CCSG) awarded by the National Cancer Institute (NCI P30CA093373) for using the flow cytometer.

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  1. Department of Biochemistry and Molecular Medicine, University of California, Davis, Sacramento, CA, USA

    N Yokdang, J Hatakeyama, J H Wald, C Simion, D Z Chang, M M Swamynathan, K L Carraway III & C Sweeney

  2. Department of Pathology and Laboratory Medicine, University of California, Davis, Sacramento, CA, USA

    J D Tellez & M Chen

  3. Department of Dermatology, University of California, Davis, Sacramento, CA, USA

    W J Murphy

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Yokdang, N., Hatakeyama, J., Wald, J. et al. LRIG1 opposes epithelial-to-mesenchymal transition and inhibits invasion of basal-like breast cancer cells. Oncogene 35, 2932–2947 (2016). https://doi.org/10.1038/onc.2015.345

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