In search of autophagy biomarkers in breast cancer: Receptor status and drug agnostic transcriptional changes during autophagy flux in cell lines

Journal Article · 05 January 2022 · PLoS ONE

DOI: https://doi.org/10.1371/journal.pone.0262134 · OSTI ID:1904973

Mascia, Francesca ^[1]; Mazo, Ilya ^[2]; Alterovitz, Wei-Lun  ^[2]; Karagiannis, Konstantinos ^[2]; Wu, Wells W. ^[2]; Shen, Rong-Fong ^[2]; Beaver, Julia A. ^[3]; Rao, V. Ashutosh  ^[2]

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1. U.S. Food and Drug Administration (FDA), Silver Spring, MD (United States). Center for Drug Evaluation and Research (CDER); OSTI
2. U.S. Food and Drug Administration (FDA), Silver Spring, MD (United States). Center for Drug Evaluation and Research (CDER)
3. U.S. Food and Drug Administration (FDA), Silver Spring, MD (United States). Oncology Center of Excellence

Autophagy drives drug resistance and drug-induced cancer cell cytotoxicity. Targeting the autophagy process could greatly improve chemotherapy outcomes. The discovery of specific inhibitors or activators has been hindered by challenges with reliably measuring autophagy levels in a clinical setting. We investigated drug-induced autophagy in breast cancer cell lines with differing ER/PR/Her2 receptor status by exposing them to known but divergent autophagy inducers each with a unique molecular target, tamoxifen, trastuzumab, bortezomib or rapamycin. Differential gene expression analysis from total RNA extracted during the earliest sign of autophagy flux showed both cell- and drug-specific changes. We analyzed the list of differentially expressed genes to find a common, cell- and drug-agnostic autophagy signature. Twelve mRNAs were significantly modulated by all the drugs and 11 were orthogonally verified with Q-RT-PCR (Klhl24, Hbp1, Crebrf, Ypel2, Fbxo32, Gdf15, Cdc25a, Ddit4, Psat1, Cd22, Ypel3). The drug agnostic mRNA signature was similarly induced by a mitochondrially targeted agent, MitoQ. In-silico analysis on the KM-plotter cancer database showed that the levels of these mRNAs are detectable in human samples and associated with breast cancer prognosis outcomes of Relapse-Free Survival in all patients (RSF), Overall Survival in all patients (OS), and Relapse-Free Survival in ER⁺ Patients (RSF ER⁺). High levels of Klhl24, Hbp1, Crebrf, Ypel2, CD22 and Ypel3 were correlated with better outcomes, whereas lower levels of Gdf15, Cdc25a, Ddit4 and Psat1 were associated with better prognosis in breast cancer patients. This gene signature uncovers candidate autophagy biomarkers that could be tested during preclinical and clinical studies to monitor the autophagy process.

• Research Organization: Oak Ridge Inst. for Science and Education (ORISE), Oak Ridge, TN (United States)
• Sponsoring Organization: U.S. Food and Drug Administration (FDA); USDOE Office of Science (SC)
• Grant/Contract Number: SC0014664
• OSTI ID: 1904973
• Journal Information: PLoS ONE, Journal Name: PLoS ONE Journal Issue: 1 Vol. 17; ISSN 1932-6203
• Publisher: Public Library of ScienceCopyright Statement
• Country of Publication: United States
• Language: English