Modulating cancer stemness provides luminal a breast cancer cells with HER2 positive-like features

Breast cancers can be classified into luminal A, luminal B, HER2 positive and triple-negative subtypes, each with a distinct therapeutic response. Tumor stemness drives cancer malignancy that challenges cancer control. Understanding the revolutionary relationships driven by tumor stemness among breast cancer subtypes is fundamental to identifying feasible therapeutic modalities for each breast cancer subtype. Utilizing the endogenous tRNA-processing system, we established a multiplexing CRISPR/dCas9 system in breast cancer cells, and applied it to a four-gene panel controlling cell potency, i.e., OCT4, KLF, MYC, SOX2. The stable cell strain, OKMS#1 was obtained through concomitantly over-expressing these genes in luminal A breast cancer cells. OKMS#1 cells showed increased invasion, proliferation and cancer stemness, shared similar drug response pattern with HER2 positive cells, and exhibited altered MAPK and enhanced NFkB signaling. This study contributes in providing an efficient multiplexing CRISPR/dCas9 system that enriches our genetic modulation tool box, and suggests that HER2 positive cells are potential progenitors of luminal A cells and that these two breast cancer subtypes may share similar treatment strategies once rewired between the two states. Our results also implicate that triple negative breast cancer cells, though sharing similar cancer stemness with HER2 positive cells, represent a distinct type of disease and require unique treatment solutions.