Re-epithelialization of cancer cells increases autophagy and DNA damage: Implications for breast cancer dormancy and relapse. Journal Articles uri icon

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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 OVOL1 (and of OVOL2 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, C1ORF116, 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.

authors

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

publication date

  • April 22, 2025