Nooshin Hashemi-Sadraei1,2, Gaëlle M Müller-Greven3, Fadi W Abdul-Karim4, Ilya Ulasov5,6, Erinn Downs-Kelly4, Monica E Burgett3, Adam Lauko3, Maha A Qadan3, Robert J Weil7,8, Manmeet S Ahluwalia7, Lingling Du9,10, Richard A Prayson4, Samuel T Chao11, Thomas G Budd1, Jill Barnholtz-Sloan12, Amy S Nowacki13, Ruth A Keri12,14, Candece L Gladson15,16. 1. Department of Solid Tumor Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA. 2. Division of Hematology and Medical Oncology, The Vontz Center for Molecular Studies, University of Cincinnati, 3125 Eden Avenue, Cincinnati, OH, 45267, USA. 3. Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, NB40, Cleveland, OH, 44195, USA. 4. Department of Pathology, Cleveland Clinic, Cleveland, OH, USA. 5. Department of Medicine, Section of Neurological Surgery, The University of Chicago, Chicago, IL, USA. 6. Center for Advanced Brain Tumor Research, Swedish Neuroscience Institute, James Tower, Suite 570, 550 17th Ave., Seattle, WA, 98122, USA. 7. Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, OH, USA. 8. Catholic Health Initiative, 198 Inverness Drive West, Englewood, CO, 80122, USA. 9. Department of Medicine, Cleveland Clinic, Cleveland, OH, USA. 10. Benson Cancer Center, Ochsner Clinic Foundation, 1514 Jefferson Highway, New Orleans, LA, 70121, USA. 11. Department of Radiation Oncology, Cleveland Clinic, Cleveland, OH, USA. 12. Division of General Medical Sciences-Oncology, Case Western Reserve University School of Medicine, Cleveland, OH, USA. 13. Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, USA. 14. Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, OH, USA. 15. Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, NB40, Cleveland, OH, 44195, USA. gladsoc@ccf.org. 16. Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, OH, USA. gladsoc@ccf.org.
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.
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 cancerpatients.
Entities:
Keywords:
Autophagy; Brain metastases of breast cancer; FIP200/Atg17; LC3; Recurrence; Survival
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