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A positive feedback loop of ER-α36/EGFR promotes malignant growth of ER-negative breast cancer cells

Oncogene volume 30, pages 770–780 (2011)Cite this article

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Abstract

It is prevailingly thought that estrogen signaling is not involved in development of estrogen receptor (ER)-negative breast cancer. However, there is evidence indicating that ovariectomy prevents the development of both ER-positive and -negative breast cancer, suggesting that estrogen signaling is involved in the development of ER-negative breast cancer. Previously, our laboratory cloned a variant of ER-α, ER-α36, and found that ER-α36 mediated nongenomic estrogen signaling and is highly expressed in ER-negative breast cancer cells. In this study, we found that ER-α36 was highly expressed in 10/12 cases of triple-negative breast cancer. We investigated the role of mitogenic estrogen signaling mediated by ER-α36 in malignant growth of triple-negative breast cancer MDA-MB-231 and MDA-MB-436 cells that express high levels of ER-α36 and found that these cells strongly responded to mitogenic estrogen signaling both in vitro and in vivo. Knockdown of ER-α36 expression in these cells using the small hairpin RNA method diminished their responsiveness to estrogen. ER-α36 physically interacted with the EGFR/Src/Shc complex and mediated estrogen-induced phosphorylation of epidermal growth factor receptor (EGFR) and Src. EGFR signaling activated ER-α36 transcription through an AP1 site in the ER-α36 promoter, and ER-α36 expression was able to stabilize EGFR protein. Our results, thus demonstrated that ER-α36 mediates nongenomic estrogen signaling through the EGFR/Src/ERK signaling pathway in ER-negative breast cancer cells and suggested that a subset of ER-negative breast tumors that expresses ER-α36, retains responsiveness to mitogenic estrogen signaling.

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Acknowledgements

This work was supported by National Institute of Health Grant DK84328 and by the Nebraska Tobacco Settlement Biomedical Research Program Award (LB-595 and LB692) to ZY Wang. Dr Semir Vranic was a research fellow at Creighton University Medical School, Omaha, NE, USA and had been supported by a UICC American Cancer Society Beginning Investigators Fellowship (ACSBI) (ACS/08/004) funded by the American Cancer Society.

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Authors and Affiliations

  1. Department of Medical Microbiology & Immunology, Creighton University Medical School, Omaha, NE, USA

    X T Zhang, L G Kang & Z-Y Wang

  2. Department of Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, PR China

    L Ding

  3. Department of Pathology, Creighton University Medical School, Omaha, NE, USA

    S Vranic, Z Gatalica & Z-Y Wang

  4. Department of Pathology, Clinical Center of the University of Sarajevo, Sarajevo, Bosnia and Herzegovina

    S Vranic

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  1. X T Zhang
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  2. L G Kang
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  4. S Vranic
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  5. Z Gatalica
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  6. Z-Y Wang
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Correspondence to Z-Y Wang.

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Zhang, X., Kang, L., Ding, L. et al. A positive feedback loop of ER-α36/EGFR promotes malignant growth of ER-negative breast cancer cells. Oncogene 30, 770–780 (2011). https://doi.org/10.1038/onc.2010.458

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