Re-epithelialization of cancer cells increases autophagy and DNA damage: Implications for breast cancer dormancy and relapse

Cellular plasticity mediates tissue development as well as cancer growth and progression. In breast cancer, a shift to a more epithelial phenotype (epithelialization) underlies a state of reversible cell growth arrest called tumor dormancy, which enables drug resistance, tumor recurrence, and metastasis. Here, we explored the mechanisms driving epithelialization and dormancy in aggressive mesenchymal-like breast cancer cells in three-dimensional cultures. Overexpressing either of the epithelial lineage-associated transcription factors OVOL1 or OVOL2 suppressed cell proliferation and migration and promoted transition to an epithelial morphology. The expression of <i>OVOL1</i> (and of <i>OVOL2</i> to a lesser extent) was regulated by steroid hormones and growth factors and was more abundant in tumors than in normal mammary cells. An uncharacterized and indirect target of OVOL1/2, <i>C1ORF116</i>, exhibited genetic and epigenetic aberrations in breast tumors, and its expression correlated with poor prognosis in patients. We further found that C1ORF116 was an autophagy receptor that directed the degradation of antioxidant proteins, including thioredoxin. Through C1ORF116 and unidentified mediators, OVOL1 expression dysregulated both redox homeostasis (in association with increased ROS, decreased glutathione, and redistribution of the transcription factor NRF2) and DNA damage and repair (in association with increased DNA oxidation and double-strand breaks and an altered interplay among the kinases p38-MAPK, ATM, and others). Because these effects, as they accumulate in cells, can promote metastasis and dormancy escape, the findings suggest that OVOLs not only promote dormancy entry and maintenance in breast cancer but also may ultimately drive dormancy exit and tumor recurrence.

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Journal
Science Signaling
Published
2025-04-22
DOI
https://doi.org/10.1126/scisignal.ado3473
Citations
5
Primary Topic
Epigenetics and DNA Methylation
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article
Field-Weighted Citation Impact
4.03
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article

Re-epithelialization of cancer cells increases autophagy and DNA damage: Implications for breast cancer dormancy and relapse

Oscar M. Rueda, Francesco Roncato, R. Alon, Eli Pikarsky et al.
5 citations
Science Signaling
Epigenetics and DNA Methylation
4.03
article

Re-epithelialization of cancer cells increases autophagy and DNA damage: Implications for breast cancer dormancy and relapse

Oscar M. Rueda, Francesco Roncato, R. Alon, Eli Pikarsky, Alessandro Genna, Moshit Lindzen, Tal Keidar Haran, Stefan Wiemann, Ron Prywes, Arturo Simoni‐Nieves, Maik Dahlhoff, Suvendu Giri, Diana Drago-García, Nishanth Ulhas Nair, Yaniv Lubling, Yosef Yarden, Sara Donzelli, Giovanni Blandino, Sima Lev, Eytan Ruppin, Rishita Chatterjee, Arunachalam Sekar, Luisa Schwarzmüller, Nooraldeen Tarade, Neel Sanghvi, Rony Seger, Harsha Raj Mohan Raju, Nishanth Belugali Nataraj, Yosef Shiloh, Carlos Caldas, Mary Luz Uribe, Nitin Gupta, Bettina Wagner, Karin Shira Bernshtein, T.P.S Bhandari, Dalit Barkan, Rong Zhu, Feride Karatekin, Maha Abedrabbo, Noa Aharoni, Agalyan Mayalagu, Yam Nof
article en
5 citations

Abstract

Cellular plasticity mediates tissue development as well as cancer growth and progression. In breast cancer, a shift to a more epithelial phenotype (epithelialization) underlies a state of reversible cell growth arrest called tumor dormancy, which enables drug resistance, tumor recurrence, and metastasis. Here, we explored the mechanisms driving epithelialization and dormancy in aggressive mesenchymal-like breast cancer cells in three-dimensional cultures. Overexpressing either of the epithelial lineage-associated transcription factors OVOL1 or OVOL2 suppressed cell proliferation and migration and promoted transition to an epithelial morphology. The expression of <i>OVOL1</i> (and of <i>OVOL2</i> to a lesser extent) was regulated by steroid hormones and growth factors and was more abundant in tumors than in normal mammary cells. An uncharacterized and indirect target of OVOL1/2, <i>C1ORF116</i>, exhibited genetic and epigenetic aberrations in breast tumors, and its expression correlated with poor prognosis in patients. We further found that C1ORF116 was an autophagy receptor that directed the degradation of antioxidant proteins, including thioredoxin. Through C1ORF116 and unidentified mediators, OVOL1 expression dysregulated both redox homeostasis (in association with increased ROS, decreased glutathione, and redistribution of the transcription factor NRF2) and DNA damage and repair (in association with increased DNA oxidation and double-strand breaks and an altered interplay among the kinases p38-MAPK, ATM, and others). Because these effects, as they accumulate in cells, can promote metastasis and dormancy escape, the findings suggest that OVOLs not only promote dormancy entry and maintenance in breast cancer but also may ultimately drive dormancy exit and tumor recurrence.

Science SignalingVol. 18(883)
Beijing Institute of Technology (CN), MODUL University Vienna (AT), Tel Aviv University (IL), German Cancer Research Center (DE), Heidelberg University (DE), Cancer Research UK Cambridge Center (GB), Cellworks Research (India) (IN), Concern Foundation (US), National Cancer Institute (MY), MRC Biostatistics Unit (GB), National Cancer Institute (US), Weizmann Institute of Science (IL), Columbia University (US), Epigenomics (Germany) (DE), University of Haifa (IL)
Good health and well-being
Openalex Percentile: Top 6%
Epigenetics and DNA Methylation
4.03
DOISourceOpenAlex
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