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Anticipatory estrogen activation of the unfolded protein response is linked to cell proliferation and poor survival in estrogen receptor α-positive breast cancer

Oncogene volume 34, pages 3760–3769 (2015)Cite this article

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Abstract

In response to cell stress, cancer cells often activate the endoplasmic reticulum (EnR) stress sensor, the unfolded protein response (UPR). Little was known about the potential role in cancer of a different mode of UPR activation, anticipatory activation of the UPR prior to accumulation of unfolded protein or cell stress. We show that estrogen, acting via estrogen receptor α (ERα), induces rapid anticipatory activation of the UPR, resulting in increased production of the antiapoptotic chaperone BiP/GRP78, preparing cancer cells for the increased protein production required for subsequent estrogen–ERα-induced cell proliferation. In ERα-containing cancer cells, the estrogen, 17β-estradiol (E2) activates the UPR through a phospholipase C γ (PLCγ)-mediated opening of EnR IP3R calcium channels, enabling passage of calcium from the lumen of the EnR into the cytosol. siRNA knockdown of ERα blocked the estrogen-mediated increase in cytosol calcium and UPR activation. Knockdown or inhibition of PLCγ, or of IP3R, strongly inhibited the estrogen-mediated increases in cytosol calcium, UPR activation and cell proliferation. E2-ERα activates all three arms of the UPR in breast and ovarian cancer cells in culture and in a mouse xenograft. Knockdown of ATF6α, which regulates UPR chaperones, blocked estrogen induction of BiP and strongly inhibited E2-ERα-stimulated cell proliferation. Mild and transient UPR activation by estrogen promotes an adaptive UPR response that protects cells against subsequent UPR-mediated apoptosis. Analysis of data from ERα+ breast cancers demonstrates elevated expression of a UPR gene signature that is a powerful new prognostic marker tightly correlated with subsequent resistance to tamoxifen therapy, reduced time to recurrence and poor survival. Thus, as an early component of the E2-ERα proliferation program, the mitogen estrogen, drives rapid anticipatory activation of the UPR. Anticipatory activation of the UPR is a new role for estrogens in cancer cell proliferation and resistance to therapy.

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Acknowledgements

We thank Mr J Hartman for assistance with xenografts, and Dr S Kaufmann and Dr K Korach for cell lines. This work was supported by NIH RO1DK 071909 (to DS) and Westcott and Carter predoctoral fellowships (to NA). Analyses were performed using BRB-ArrayTools, developed by Dr Richard Simon and BRB-ArrayTools Development Team at the National Cancer Institute.

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Authors and Affiliations

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

    N Andruska, X Zheng & D J Shapiro

  2. College of Medicine, University of Illinois, Urbana, IL, USA

    N Andruska, W G Helferich & D J Shapiro

  3. Department of Food Science and Human Nutrition, University of Illinois, Urbana, IL, USA

    X Yang & W G Helferich

  4. University of Illinois Cancer Center, Urbana, IL, USA

    W G Helferich & D J Shapiro

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  1. N Andruska
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Correspondence to D J Shapiro.

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Andruska, N., Zheng, X., Yang, X. et al. Anticipatory estrogen activation of the unfolded protein response is linked to cell proliferation and poor survival in estrogen receptor α-positive breast cancer. Oncogene 34, 3760–3769 (2015). https://doi.org/10.1038/onc.2014.292

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