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Mouse ER+/PIK3CAH1047R breast cancers caused by exogenous estrogen are heterogeneously dependent on estrogen and undergo BIM-dependent apoptosis with BH3 and PI3K agents

Oncogenevolume 38pages4759 (2019) | Download Citation

Abstract

Estrogen dependence is major driver of ER + breast cancer, which is associated with PI3K mutation. PI3K inhibition (PI3Ki) can restore dependence on ER signaling for some hormone therapy-resistant ER + breast cancers, but is ineffective in others. Here we show that short-term supplementation with estrogen strongly enhanced Pik3caH1047R−induced mammary tumorigenesis in mice that resulted exclusively in ER + tumors, demonstrating the cooperation of the hormone and the oncogene in tumor development. Similar to human ER + breast cancers that are endocrine-dependent or endocrine-independent at diagnosis, tumor lines from this model retained ER expression but were sensitive or resistant to hormonal therapies. PI3Ki did not induce cell death but did cause upregulation of the pro-apoptotic gene BIM. BH3 mimetics or PI3Ki were unable to restore hormone sensitivity in several resistant mouse and human tumor lines. Importantly however, combination of PI3Ki and BH3 mimetics had a profound, BIM-dependent cytotoxic effect in PIK3CA-mutant cancer cells while sparing normal cells. We propose that addition of BH3 mimetics offers a therapeutic strategy to markedly improve the cytotoxic activity of PI3Ki in hormonal therapy-resistant and ER−independent PIK3CA-mutant breast cancer.

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Acknowledgements

We would like to thank Stuart Aaronson and Jerry Chipuk for providing reagents and helpful discussions, Xi Sun for technical assistance and all members of the Parsons laboratory for critical reading of the manuscript. We also thank the Stand Up To Cancer (SU2C) PI3K Dream Team for providing BYL719. This work was supported by the Komen Foundation Scholar Award SAC110028 and NCI R01 CA129432 to R. Parsons. Additional support was given to E. Stratikopoulos from the Department of Defense Breast Cancer Research Program Era of Hope Award BC087596.

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  1. Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    • Elias E. Stratikopoulos
    • , Nicole Kiess
    • , Sarah Pegno
    • , Cheung Kakit
    • , Xuewei Wu
    • , Poulikos I. Poulikakos
    • , Pamela Cheung
    •  & Ramon Parsons
  2. Department of Pathology, Columbia University Medical Center, New York, NY, 10032, USA

    • Matthias Szabolcs
  3. Department of Surgery, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    • Hank Schmidt

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The authors declare that they have no conflict of interest.

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Correspondence to Ramon Parsons.

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https://doi.org/10.1038/s41388-018-0436-4