Let-7 miRNAs sensitize breast cancer stem cells to radiation-induced repression through inhibition of the cyclin D1/Akt1/Wnt1 signaling pathway

The tumor-suppressive let-7 family of microRNAs (miRNAs) has been previously identified to induce cell apoptosis, proliferation-inhibition and suppression of the self-renewal capacities of cancer stem cells (CSCs). However, let-7-mediated sensitization of tumors to radiation treatment remains to be investigated fully in triple negative breast cancer (TNBC), of which the clinical treatment is challenging. The inhibitory effect of let-7 miRNAs on the self-renewal ability of CSCs from TNBC was investigated. It was identified that radiation inhibited the self-renewal ability of TNBC stem cells by inhibiting cyclin D1 and protein kinase B (Akt1) phosphorylation. Let-7d stimulates radiation-induced tumor repression, exerting synergistic effects with radiotherapy on stem cell renewal. Through western blotting, immunofluorescence and a luciferase assay, it was identified that reduced cyclin D1/Akt1/wingless type MMTV integration site family member 1 (Wnt1) signaling activity accounts for the let-7-induced radiation sensitization. Let-7 directly inhibits cyclin D1 expression, resulting in low phosphorylation of Akt1, which is critical for the let-7-induced inhibition of mammosphere numbers. The let-7d-induced Akt1 inhibition contributed to tumor repression, with similar results to those obtained with Akt inhibitors. Furthermore, it was identified that the inhibition of Wnt1 is critical for the functioning of let-7d, and that addition of recombinant Wnt1 abolished the effects of let-7d on sensitization to radiotherapy. Let-7d is suggested to be a promising therapeutic agent in the treatment of TNBC by targeting CSCs and sensitizing tumors to radiotherapy via inhibition of cyclin D1/Akt1/Wnt1 signaling.