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Progesterone Receptor Gene Variants in Metastatic Estrogen Receptor Positive Breast Cancer

  • Amy M. FowlerEmail author
  • Kelley Salem
  • Michael DeGrave
  • Irene M. Ong
  • Shane Rassman
  • Ginny L. Powers
  • Manoj Kumar
  • Ciara J. Michel
  • Aparna M. Mahajan
Original Paper

Abstract

Tumor mutations in the gene encoding estrogen receptor alpha (ESR1) have been identified in metastatic breast cancer patients with endocrine therapy resistance. However, relatively little is known about the occurrence of mutations in the progesterone receptor (PGR) gene in this population. The study objective was to determine the frequency and prognostic significance of tumor PGR mutations for patients with estrogen receptor (ER)-positive metastatic breast cancer. Thirty-five women with metastatic or locally recurrent ER+ breast cancer were included in this IRB-approved, retrospective study. Targeted next-generation sequencing of the PGR gene was performed on isolated tumor DNA. Associations between mutation status and clinicopathologic factors were analyzed as well as overall survival (OS) from time of metastatic diagnosis. The effect of the PGR variant Y890C (c.2669A>G) identified in this cohort on PR transactivation function was tested using ER−PR− (MDA-MB-231), ER+PR+ (T47D), and ER+PR− (T47D PR KO) breast cancer cell lines. There were 71 occurrences of protein-coding PGR variants in 67% (24/36; 95% CI 49–81%) of lesions. Of the 49 unique variants, 14 are single nucleotide polymorphisms (SNPs). Excluding SNPs, the median OS of patients with PGR variants was 32 months compared to 79 months with wild-type PGR (p = 0.42). The most frequently occurring (4/36 lesions) non-SNP variant was Y890C. Cells expressing Y890C had reduced progestin-stimulated PR transactivation compared to cells expressing wild-type PR. PGR variants occur frequently in ER+ metastatic breast cancer. Although some variants are SNPs, others are predicted to be functionally deleterious as demonstrated with Y890C PR.

Keywords

Breast cancer PGR Gene variants Next-generation sequencing Tumor mutations Progesterone receptor 

Notes

Acknowledgments

The authors thank the University of Wisconsin Biotechnology Center DNA Sequencing Facility for providing library preparation and next generation sequencing services. We also thank the UW Translational Research Initiatives in Pathology Lab for technical assistance and the University of Wisconsin Carbone Cancer Center Support Grant P30 CA014520. Also, we thank Derek M. Pavelec, PhD and the University of Wisconsin Carbone Cancer Center Computational Informatics Shared Resource for assistance in sequencing data analysis. We also thank the University of Wisconsin Optical Imaging Core for confocal microscopy and image collection. Lastly, we thank J. Julie Kim, PhD (Northwestern University) for generously providing the T47D PR KO cell line.

Funding Information

This work was supported by the University of Wisconsin Paul P. Carbone Cancer Center Young Investigator Award, the University of Wisconsin Institute of Clinical and Translational Research KL2 Scholar Award, 1KL2TR002374, the Clinical and Translational Science Award program, grant 1UL1TR002373, the University of Wisconsin School of Medicine and Public Health Shapiro Summer Research Program, and the University of Wisconsin Department of Radiology.

Supplementary material

12672_2020_377_MOESM1_ESM.docx (46 kb)
ESM 1 (DOCX 45 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2020

Authors and Affiliations

  • Amy M. Fowler
    • 1
    • 2
    • 3
    Email author
  • Kelley Salem
    • 1
  • Michael DeGrave
    • 1
  • Irene M. Ong
    • 2
    • 4
    • 5
  • Shane Rassman
    • 1
  • Ginny L. Powers
    • 1
  • Manoj Kumar
    • 1
  • Ciara J. Michel
    • 1
  • Aparna M. Mahajan
    • 6
  1. 1.Department of RadiologyUniversity of Wisconsin School of Medicine and Public HealthMadisonUSA
  2. 2.University of Wisconsin Carbone Cancer CenterMadisonUSA
  3. 3.Department of Medical PhysicsUniversity of Wisconsin School of Medicine and Public HealthMadisonUSA
  4. 4.Department of Obstetrics and GynecologyUniversity of Wisconsin School of Medicine and Public HealthMadisonUSA
  5. 5.Department of Biostatistics and Medical InformaticsUniversity of Wisconsin School of Medicine and Public HealthMadisonUSA
  6. 6.Department of Pathology and Laboratory MedicineUniversity of Wisconsin School of Medicine and Public HealthMadisonUSA

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