52P - A siRNA screen to re-activate senescence in basal-like breast cancer

Date 07 May 2015
Event IMPAKT 2015
Session Welcome reception and Poster Walk
Topics Breast Cancer
Translational Research
Presenter Madeleine Moore
Citation Annals of Oncology (2015) 26 (suppl_3): 15-24. 10.1093/annonc/mdv117
Authors M. Moore, M. Philpott, C. Bishop
  • The Centre For Cutaneous Research, The Blizard Institute, Queen Mary University of London, E1 2AT - London/UK



Oncogene-induced senescence (OIS) is a key tumour suppressor mechanism and the bypass of OIS is an essential step on the path towards carcinogenesis. As such, re-activating senescence in cancer is an attractive therapeutic strategy and one that is gaining momentum. p16-positive basal-like breast cancer (p16+ BLBC) is an aggressive disease subtype, often associated with a poor prognosis due to the lack of effective treatments available. In order to tackle this and identify the genes that govern senescence evasion in p16+ BLBC, a genome‐wide siRNA screen and two subsequent validation screens in the p16+ BLBC cell line, MDA‐MB‐468, were performed. A significant reduction in proliferation, together with a significant increase in cell area was used to define senescence induction. The data generated was then compared to a previously published screen in primary human mammary epithelial cells (HMECs) (Bishop et al., Molecular Cell 2010). This revealed 25 siRNAs that re-activated senescence in MDA-MB-468 cells but had no effect on the proliferation or morphology of HMECs. Strikingly, 11 of the 25 siRNAs identified target ribosomal proteins (RPs) (components of the ribosome). This data implicates dysregulated ribosomal biosynthesis in cancer and indicates that targeting the ribosome could be highly effective at re-activating senescence in p16+ BLBC. Importantly, analysis of the METABRIC data set indicated that many of these RPs were often overexpressed in p16-positive BLBC. In addition, Kaplan-Meier analysis revealed that elevated expression of six of the 11 RPs correlates with a reduced overall survival in BLBC patients, further supporting a role for these RPs as drivers of disease. It is hoped these candidates may form the basis of a novel targeted therapy in p16+ BLBC. Finally, examination of the nucleolus (the primary site for ribosomal biosynthesis) indicated that senescence re-activation following RP knockdown resulted in significant changes to nucleolar morphology. In addition, the METABRIC data set revealed that nucleolin (nucleolar phosphoprotein) was often overexpressed in p16+ BLBC. We propose, that once validated, the nucleoli signature, potentially in combination with the RPs, may act as a novel prognostic biomarker in p16+ BLBC.

Disclosure: All authors have declared no conflicts of interest.