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Journal of Neuro-Oncology

, Volume 140, Issue 2, pp 237–248 | Cite as

Expression of LC3B and FIP200/Atg17 in brain metastases of breast cancer

  • Nooshin Hashemi-Sadraei
  • Gaëlle M. Müller-Greven
  • Fadi W. Abdul-Karim
  • Ilya Ulasov
  • Erinn Downs-Kelly
  • Monica E. Burgett
  • Adam Lauko
  • Maha A. Qadan
  • Robert J. Weil
  • Manmeet S. Ahluwalia
  • Lingling Du
  • Richard A. Prayson
  • Samuel T. Chao
  • Thomas G. Budd
  • Jill Barnholtz-Sloan
  • Amy S. Nowacki
  • Ruth A. Keri
  • Candece L. Gladson
Laboratory Investigation

Abstract

Background

Macroautophagy/autophagy is considered to play key roles in tumor cell evasion of therapy and establishment of metastases in breast cancer. High expression of LC3, a residual autophagy marker, in primary breast tumors has been associated with metastatic disease and poor outcome. FIP200/Atg17, a multi-functional pro-survival molecule required for autophagy, has been implicated in brain metastases in experimental models. However, expression of these proteins has not been examined in brain metastases from patients with breast cancer.

Methods

In this retrospective study, specimens from 44 patients with brain metastases of infiltrating ductal carcinoma of the breast (IDC), unpaired samples from 52 patients with primary IDC (primary-BC) and 16 matched-paired samples were analyzed for LC3 puncta, expression of FIP200/Atg17, and p62 staining.

Results

LC3-puncta+ tumor cells and FIP200/Atg17 expression were detected in greater than 90% of brain metastases but there were considerable intra- and inter-tumor differences in expression levels. High numbers of LC3-puncta+ tumor cells in brain metastases correlated with a significantly shorter survival time in triple-negative breast cancer. FIP200/Atg17 protein levels were significantly higher in metastases that subsequently recurred following therapy. The percentages of LC3 puncta+ tumor cells and FIP200/Atg17 protein expression levels, but not mRNA levels, were significantly higher in metastases than primary-BC. Meta-analysis of gene expression datasets revealed a significant correlation between higher FIP200(RB1CC1)/Atg17 mRNA levels in primary-BC tumors and shorter disease-free survival.

Conclusions

These results support assessments of precision medicine-guided targeting of autophagy in treatment of brain metastases in breast cancer patients.

Keywords

Brain metastases of breast cancer Autophagy LC3 FIP200/Atg17 Survival Recurrence 

Notes

Acknowledgements

We thank Dr. Maciej Lesniak (UCH) for FFPE sections of BCBM and the primary breast cancer TMA. This work was supported by awards from the Cleveland Clinic RPC 2010-1070-R1 (NHS); R01-CA152883 and R01-CA175120 (CLG); and the METavivor Foundation (CLG, RAK).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

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Supplementary material 1 (DOCX 18 KB)
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Supplementary material 3 (DOCX 477 KB)
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Supplementary material 4 (DOCX 2302 KB)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Nooshin Hashemi-Sadraei
    • 1
    • 11
  • Gaëlle M. Müller-Greven
    • 2
  • Fadi W. Abdul-Karim
    • 3
  • Ilya Ulasov
    • 10
    • 12
  • Erinn Downs-Kelly
    • 3
  • Monica E. Burgett
    • 2
  • Adam Lauko
    • 2
  • Maha A. Qadan
    • 2
  • Robert J. Weil
    • 4
    • 13
  • Manmeet S. Ahluwalia
    • 4
  • Lingling Du
    • 5
    • 14
  • Richard A. Prayson
    • 3
  • Samuel T. Chao
    • 7
  • Thomas G. Budd
    • 1
  • Jill Barnholtz-Sloan
    • 8
  • Amy S. Nowacki
    • 6
  • Ruth A. Keri
    • 8
    • 9
  • Candece L. Gladson
    • 2
    • 4
  1. 1.Department of Solid Tumor Oncology, Taussig Cancer InstituteCleveland ClinicClevelandUSA
  2. 2.Department of Cancer Biology, Lerner Research InstituteCleveland ClinicClevelandUSA
  3. 3.Department of PathologyCleveland ClinicClevelandUSA
  4. 4.Brain Tumor and Neuro-Oncology CenterCleveland ClinicClevelandUSA
  5. 5.Department of MedicineCleveland ClinicClevelandUSA
  6. 6.Quantitative Health SciencesCleveland ClinicClevelandUSA
  7. 7.Department of Radiation OncologyCleveland ClinicClevelandUSA
  8. 8.Division of General Medical Sciences-OncologyCase Western Reserve University School of MedicineClevelandUSA
  9. 9.Department of PharmacologyCase Western Reserve University School of MedicineClevelandUSA
  10. 10.Department of Medicine, Section of Neurological SurgeryThe University of ChicagoChicagoUSA
  11. 11.Division of Hematology and Medical Oncology, The Vontz Center for Molecular StudiesUniversity of CincinnatiCincinnatiUSA
  12. 12.Center for Advanced Brain Tumor ResearchSwedish Neuroscience InstituteSeattleUSA
  13. 13.Catholic Health InitiativeEnglewoodUSA
  14. 14.Benson Cancer CenterOchsner Clinic FoundationNew OrleansUSA

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