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Ubiquitin ligase RNF8 suppresses Notch signaling to regulate mammary development and tumorigenesis. 2018
Li Li, and
Kiran Kumar Naidu Guturi, and
Brandon Gautreau, and
Parasvi S Patel, and
Amine Saad, and
Mayako Morii, and
Francesca Mateo, and
Luis Palomero, and
Haithem Barbour, and
Antonio Gomez, and
Deborah Ng, and
Max Kotlyar, and
Chiara Pastrello, and
Hartland W Jackson, and
Rama Khokha, and
Igor Jurisica, and
El Bachir Affar, and
Brian Raught, and
Otto Sanchez, and
Moulay Alaoui-Jamali, and
Miguel A Pujana, and
Anne Hakem, and
Razq Hakem
Princess Margaret Cancer Centre, University Health Network and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
The E3 ubiquitin ligase RNF8 plays critical roles in maintaining genomic stability by promoting the repair of DNA double-strand breaks (DSBs) through ubiquitin signaling. Abnormal activation of Notch signaling and defective repair of DSBs promote breast cancer risk. Here, we found that low expression of the full-length RNF8 correlated with poor prognosis for breast cancer patients. Our data revealed that in addition to its role in the repair of DSBs, RNF8 regulated Notch1 signaling and cell-fate determination of mammary luminal progenitors. Mechanistically, RNF8 acted as a negative regulator of Notch signaling by ubiquitylating the active NOTCH1 protein (N1ICD), leading to its degradation. Consistent with abnormal activation of Notch signaling and impaired repair of DSBs in Rnf8-mutant mammary epithelial cells, we observed increased risk of mammary tumorigenesis in mouse models for RNF8 deficiency. Notably, deficiency of RNF8 sensitized breast cancer cells to combination of pharmacological inhibitors of Notch signaling and poly(ADP-ribose) polymerase (PARP), suggesting implications for treatment of breast cancer associated with impaired RNF8 expression or function.
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