Effective targeting of breast cancer stem cells by combined inhibition of Sam68 and Rad51

Alice Turdo, Miriam Gaggianesi, Simone Di Franco, Veronica Veschi, Caterina D’Accardo, Gaetana Porcelli, Melania Lo Iacono, Irene Pillitteri, Francesco Verona, Gabriella Militello, Alessio Zippo, Vittoria Poli, Luca Fagnocchi, Sven Beyes, Stefania Stella, Rossano Lattanzio, Naida Faldetta, Vincenzo L. Lentini, Rossana Porcasi, Giuseppe PistoneMaria Rita Bongiorno, Giorgio Stassi, Ruggero De Maria Marchiano, Matilde Todaro

Risultato della ricerca: Contributo in rivistaArticolo in rivista


Breast cancer (BC) is the second cause of cancer-related deceases in the worldwide female population. Despite the successful treatment advances, 25% of BC develops resistance to current therapeutic regimens, thereby remaining a major hurdle for patient management. Current therapies, targeting the molecular events underpinning the adaptive resistance, still require effort to improve BC treatment. Using BC sphere cells (BCSphCs) as a model, here we showed that BC stem-like cells express high levels of Myc, which requires the presence of the multifunctional DNA/RNA binding protein Sam68 for the DNA-damage repair. Analysis of a cohort of BC patients displayed that Sam68 is an independent negative factor correlated with the progression of the disease. Genetic inhibition of Sam68 caused a defect in PARP-induced PAR chain synthesis upon DNA-damaging insults, resulting in cell death of TNBC cells. In contrast, BC stem-like cells were able to survive due to an upregulation of Rad51. Importantly, the inhibition of Rad51 showed synthetic lethal effect with the silencing of Sam68, hampering the cell viability of patient-derived BCSphCs and stabilizing the growth of tumor xenografts, including those TNBC carrying BRCA mutation. Moreover, the analysis of Myc, Sam68 and Rad51 expression demarcated a signature of a poor outcome in a large cohort of BC patients. Thus, our findings suggest the importance of targeting Sam68-PARP1 axis and Rad51 as potential therapeutic candidates to counteract the expansion of BC cells with an aggressive phenotype.
Lingua originaleEnglish
pagine (da-a)2196-2209
Numero di pagine14
Stato di pubblicazionePubblicato - 2022


  • Adaptor Proteins, Signal Transducing
  • Breast Neoplasms
  • Cell Cycle Proteins
  • Cell Line, Tumor
  • DNA Repair
  • DNA-Binding Proteins
  • Female
  • Humans
  • Neoplastic Stem Cells
  • RNA-Binding Proteins
  • Rad51 Recombinase
  • Triple Negative Breast Neoplasms


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