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Interplay between the levels of estrogen and estrogen receptor controls the level of the granzyme inhibitor, proteinase inhibitor 9 and susceptibility to immune surveillance by natural killer cells

Oncogene volume 26, pages 4106–4114 (2007)Cite this article

Abstract

Estrogens promote cell proliferation and metastases in several human cancers. Here, we describe a different action of estrogens likely to contribute to tumor development-blocking immunosurveillance. In breast cancer cells, increasing concentrations of estrogen induce increasing levels of the granzyme B inhibitor, SerpinB9/proteinase inhibitor 9 (PI-9) and progressively block cell death induced by NK92 natural killer (NK) cells, but do not block killing by a second NK cell line, NKL cells. RNA interference knockdown of PI-9 abolishes estrogen's ability to block NK92 cell-induced cytotoxicity. Expressing elevated levels of estrogen receptor α (ERα) increases the induced level of PI-9, and makes tamoxifen (TAM), but not raloxifene or ICI 182,780, a potent inducer of PI-9. At elevated levels of ERα, induction of PI-9 by estradiol or TAM blocks killing by both NK92 and NKL cells. When the Erk pathway is activated with epidermal growth factor, the concentration of estrogen required to induce a protective level of PI-9 is reduced to 10 pM. Elevated concentrations of estrogen and ER may provide a dual selective advantage to breast cancer cells by controlling PI-9 levels and thereby blocking immunosurveillance. Expressing elevated levels of ERα reveals a potentially important difference in the effects of TAM, raloxifene and ICI 182,780 on immunosurveillance in breast cancer.

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Acknowledgements

We are grateful to Dr J Miller, Dr M Robertson and Dr C Froelich who generously provided the NK92, NKL and YT cell lines, respectively. Grant Support: NIH DK071909 and HD16720 (to DS) and DOD BCRF W81XH-04-1-0327 and NIH DK64034 (to EA).

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  1. Department of Biochemistry, University of Illinois, Urbana, IL, USA

    X Jiang & D J Shapiro

  2. Department of Physiology, University of Wisconsin, Madison, WI, USA

    S J Ellison & E T Alarid

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  1. X Jiang
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Correspondence to D J Shapiro.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Jiang, X., Ellison, S., Alarid, E. et al. Interplay between the levels of estrogen and estrogen receptor controls the level of the granzyme inhibitor, proteinase inhibitor 9 and susceptibility to immune surveillance by natural killer cells. Oncogene 26, 4106–4114 (2007). https://doi.org/10.1038/sj.onc.1210197

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