miR4673 improves fitness profile of neoplastic cells by induction of autophagy

Therapeutic resistance of neoplasms is mainly attributed to gradual evolution of mutational profile(1). Here, we demonstrate a microRNA-mediated mechanism that effectively improves fitness of SKBR3 mammary carcinoma cells by cytoplasmic reprogramming. The reprogramming is triggered by endogenous miR4673 transcribed from notch-1 locus. The miRNA downregulates cdk-18, a cyclin-dependent kinase that regulates M-G1 transition in cycling cells(2,3). Suppression of cdk-18 triggers mitophagy and autophagy. Due to high autophagic flux, oestrogen receptor-1(+)/progesterone receptor(+)/p53(+) (Esr1(+)/Pr(+)/p53(+)) SKBR3 cells are coerced into an Esr1(−)/Pr(low)/p53(−)profile. Increased mitophagy in combination with proteasomal degradation of p53 transiently arrests the cycling cells at G0 and enhances radio-resistance of the SKBR3 population. These findings highlight the impact on cancer therapy of non-encoded neoplastic resistance, arising as a consequence of miRNA-mediated autophagic reprogramming that uncouples phenotype and genotype.