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G1P3, an interferon- and estrogen-induced survival protein contributes to hyperplasia, tamoxifen resistance and poor outcomes in breast cancer

Oncogene volume 31, pages 2222–2236 (2012)Cite this article

Abstract

Hormonally regulated survival factors can have an important role in breast cancer. Here we elucidate G1P3, a survival protein induced by interferons (IFNs), as a target of estrogen signaling and a contributor to poor outcomes in estrogen receptor-positive (ER+) breast cancer. Compared with normal breast tissue, G1P3 was upregulated in the malignant epithelium (50 × higher) and was induced by estrogen ex vivo. In accord with its overexpression in early stages of breast cancer (hyperplasia and ductal carcinoma in situ), in morphogenesis assays G1P3 enhanced the survival of MCF10A acinar luminal cells causing hyperplasia by suppressing detachment-induced loss of mitochondrial potential and apoptosis (anoikis). In cells undergoing anoikis, G1P3 attenuated the induction of Bim protein, a proapoptotic member of the Bcl-2 family and reversed the downmodulation of Bcl-2 protein. Downregulation of G1P3 induced spontaneous apoptosis in BT-549 breast cancer cells and significantly reduced the growth of ER+ breast cancer cell MCF7 (P⩽0.01), further suggesting its prosurvival activity. In agreement with its induction by estrogen, G1P3 antagonized tamoxifen, an inhibitor of ER in MCF7 cells. More importantly, elevated expression of G1P3 was significantly associated with decreased relapse-free and overall survival in ER+ breast cancer patients (P⩽0.01). Our studies suggest that elevated expression of G1P3 may perturb canonical tumor-suppressing activity of IFNs partly by affecting the balance of pro- and antiapoptotic members of Bcl-2 family proteins, leading to breast cancer development and resistance to therapies.

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Article 23 September 2019

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Acknowledgements

This study is supported by a Clinical and Translational Science Collaborative (CTSC) award to VC and by NCI CA043703 to ECB. We thank Drs Thomas Budd and Joseph Crowe and Mrs Joanne Lyons for their help in procuring biopsies. Our sincere thanks to Dr Judith Drazba, director of the Cleveland Clinic Imaging Core, Dr John Peterson and Eric Diskin for their kind help with the confocal and light microscopy. We thank Linda Vargo for preparing the specimens for in situ hybridization. We gratefully acknowledge Dr Aejaz Nasir at Eli Lilly and Dr Tim Huang at the Ohio State University for helpful discussions. We also thank Dr George Stark and Dr Thomas Budd at the Cleveland Clinic for critical reading of the manuscript.

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  1. V Cheriyath

    Present address: 4Current address: Department of Biological and Environmental Sciences, Texas A&M University—Commerce, Commerce, TX, USA.,

Authors and Affiliations

  1. Translational Hematology and Oncology Research, Taussig Cancer Institute, The Cleveland Clinic, Cleveland, OH, USA

    V Cheriyath, M A Kuhns, B S Jacobs, P Evangelista & E C Borden

  2. Department of Quantitative Health Sciences, The Cleveland Clinic, Cleveland, OH, USA

    P Elson

  3. Department of Molecular Pathology, The Cleveland Clinic, Cleveland, OH, USA

    E Downs-Kelly & R Tubbs

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Cheriyath, V., Kuhns, M., Jacobs, B. et al. G1P3, an interferon- and estrogen-induced survival protein contributes to hyperplasia, tamoxifen resistance and poor outcomes in breast cancer. Oncogene 31, 2222–2236 (2012). https://doi.org/10.1038/onc.2011.393

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