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GATA3 inhibits lysyl oxidase-mediated metastases of human basal triple-negative breast cancer cells

Oncogene volume 31, pages 2017–2027 (2012)Cite this article

Abstract

Discovery of mechanisms that impede the aggressive and metastatic phenotype of human basal triple-negative-type breast cancers (BTNBCs) could provide novel targets for therapy for this form of breast cancer that has a relatively poor prognosis. Previous studies have demonstrated that expression of GATA3, the master transcriptional regulator of mammary luminal differentiation, can reduce the tumorigenicity and metastatic propensity of the human BTNBC MDA-MB-231 cell line (MB231), although the mechanism for reduced metastases was not elucidated. We demonstrate through gene expression profiling that GATA3 expression in 231 cells resulted in the dramatic reduction in the expression of lysyl oxidase (LOX), a metastasis-promoting, matrix-remodeling protein, in part, through methylation of the LOX promoter. Suppression of LOX expression by GATA3 was further confirmed in the BTNBC Hs578T cell line. Conversely, reduction of GATA3 expression by small interfering RNA in luminal BT474 cells increased LOX expression. Reconstitution of LOX expression in 231-GATA3 cells restored metastatic propensity. A strong inverse association between LOX and GATA3 expression was confirmed in a panel of 51 human breast cancer cell lines. Similarly, human breast cancer microarray data demonstrated that high LOX/low GATA3 expression is associated with the BTNBC subtype of breast cancer and poor patient prognosis. Expression of GATA3 reprograms BTNBCs to a less aggressive phenotype and inhibits a major mechanism of metastasis through inhibition of LOX. Induction of GATA3 in BTNBC cells or novel approaches that inhibit LOX expression or activity could be important strategies for treating BTNBCs.

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Acknowledgements

We thank Drs Lalage Wakefield and Li Yang for helpful scientific discussions. We also thank Lara El-Touny, Dalit Barkan, Zi-Yao Liu, TingHu Qiu, Anthony Vieira, Christina Bennett, Christine Tomlinson, Steven Austin, Christian Mustroph and Wei-Chu Lai for technical assistance; Paul Meltzer for sharing unpublished data; the LRBGE Fluorescence Imaging Core and Chand Khanna for the use of fluorescence microscopy equipment; and Julie Foley and Norris Flagler for technical assistance with image analysis. This research was supported in part by the Intramural Research Program, Center for Cancer Research, NCI, NIH. IMC acknowledges support from the Department of Defense Breast Cancer Research Program (W81XWH-10-2-0030).

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Authors and Affiliations

  1. Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, MD, USA

    I M Chu, A M Michalowski, D Luger, M Sato, K Flanders, A Oshima & J E Green

  2. Cellular and Molecular Pathology Branch, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA

    M Hoenerhoff

  3. John A Burns School of Medicine, University of Hawaii, Honolulu, HI, USA

    K M Szauter & K Csiszar

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  1. I M Chu
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  2. A M Michalowski
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Correspondence to J E Green.

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Chu, I., Michalowski, A., Hoenerhoff, M. et al. GATA3 inhibits lysyl oxidase-mediated metastases of human basal triple-negative breast cancer cells. Oncogene 31, 2017–2027 (2012). https://doi.org/10.1038/onc.2011.382

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