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ER–/PR+ breast cancer is controlled more effectively with an inflammatory inhibitor than hormonal inhibitor

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Abstract

Background

The anti-estrogen tamoxifen is a highly effective hormonal therapy for hormonal-positive (HR+) breast cancer patients; however, the estrogen receptor-negative, progesterone receptor-positive (ER–/PR+) subtype does not give the benefits of tamoxifen. Therefore ER–/PR+ breast cancer has a poor clinical outcome, and novel drug therapy for ER–/PR+ breast cancer could benefit these patients.

Methods

53,805 gene expressions were characterized into HR+ BC and triple-negative breast cancer (TNBC) and analyzed through Breast Cancer Gene Expression Miner in 4319 breast cancer patient samples. The clinical outcomes including overall survival, distant metastasis-free survival, and relapse-free survival were obtained from the PrognoScan database containing 1190 human breast cancer patient samples. To determine the function of ERα and inflammation-related genes such as USP1, CDC20, and CASP1, we used the CRISPR–Cas9 system or gene knockdown (KD) system. To check tumor cell proliferation and migration of ERα KO breast cancer cell line, we used tamoxifen and the inflammation inhibitor Ac-YVAD-CHO. For further confirmation, cancer growth was checked with the inflammation inhibitor in ERα KO breast cancer cell line using a three-dimensional (3D) organoid tissue culture system (ex vivo).

Results

We found that gene expression in ER−/PR+ hormonal-positive breast cancer is positively related to ER–/PR– very similar to TNBC, not other HR+ breast cancer using a 4319 breast cancer patient database. Especially, inflammation-related genes, USP1, CDC20, and CASP1, which are highly expressed in TNBC, are also upregulated in ER−/PR+ HR+ breast cancer. Suppression of USP1, CDC20, and CASP1 inhibited tumor cell growth and metastasis in ERα KO (ER–/PR +) cell lines. Interestingly, loss of ERα in HR+ cell lines is not responsive to tamoxifen, but highly sensitive to the inflammation inhibitor, Ac-YVAD-CHO. In in vitro and ex vivo (3D organoid) models, inflammation inhibitor-specific blocks ER–/PR+ tumor proliferation and migration.

Conclusions

These findings suggest that an inflammation inhibitor might be a potential option for therapy for ER–/PR+ HR breast cancer patients.

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Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors thank the Jack Kent Cooke Foundation for providing support for the experiments and data analysis. We also thank Zach Cohen (Jack Kent Cooke), Aaron Larson (Mayo High School, Rochester, MN, USA), Corinne Ehrfurth (Mayo High School, Rochester, MN, USA), Christin Stegenga (Mayo High School, Rochester, MN, USA), and JungJin Kim (Mayo Clinic, Rochester, MN, USA) for their contribution in this study.

Funding

This study was funded by the Jack Kent Cooke Foundation’s Young Scholars Program.

Author information

Authors and Affiliations

  1. Division of Radiology, Mayo Clinic, Rochester, MN, 55905, USA

    Christine Song, Ayse Tuba Kendi, Val J. Lowe & SeungBaek Lee

  2. Mayo High School, Rochester, MN, 55904, USA

    Christine Song

  3. College of Nursing, Dankook University, Cheonan, Chungcheongnam, 31116, Republic of Korea

    Ji Yeon Shim

  4. U&Hang Clinic, Asan, Chungcheongnam, 31514, Republic of Korea

    Dawa Jung & Pil Soo Kang

  5. Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, 55905, USA

    SeungBaek Lee

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  1. Christine Song
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Contributions

SBL, CS, DWJ, and JYS designed and performed most of the experiments, analyzed data, and prepared the manuscript as a lead author. PSK, ATK, and VL contributed to editing and commenting on the paper. VL and SBL supervised the project.

Corresponding authors

Correspondence to Val J. Lowe or SeungBaek Lee.

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Conflict of interest

Dr. Lowe is a consultant for AVID Radiopharmaceuticals, Eisai Co. Inc., Bayer Schering Pharma, GE Healthcare, and Merck Research, and receives research support from GE Healthcare, Siemens Molecular Imaging, AVID Radiopharmaceuticals, and NIH (NIA, NCI).

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This article does not contain any studies with human participants or animals performed by any of the authors.

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Requests for materials should be addressed to S.B.L (lee.seungbaek@mayo.edu).

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Song, C., Kendi, A.T., Shim, J.Y. et al. ER–/PR+ breast cancer is controlled more effectively with an inflammatory inhibitor than hormonal inhibitor. Breast Cancer 30, 436–452 (2023). https://doi.org/10.1007/s12282-023-01437-6

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  • DOI: https://doi.org/10.1007/s12282-023-01437-6

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