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

Abstract

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.

Assessing the prognostic value of stemness-related genes in breast cancer patients

“…In addition, CSCs also have DNA repair and antiapoptotic effects 23 , which are responsible for resistance to treatment. What’s more, different BC molecular subtypes, such as TNBC cells and HER-2 positive cells, has the similar stemness, but they are tow unique diseases that require different treatment strategies 24 . In BCSCs of different molecular subtypes, the expression and regulation of HER-2 are both different, so therapeutic repercussion and prognosis of patients will be different 25 .…”

Establishment of a type II insulin‑like growth factor receptor gene site‑integrated SKBR3 cell line using CRISPR/Cas9

“…Low PinX1 expression is associated the malignant behavior of these cells. Mei et al ( 27 ) successfully designed an efficient multiplexed CRISPR/dCas9 system using CRISPR/Cas9 technology, and applied it to study the phylogenetic relationship between breast cancer subtypes driven by cancer stems, and clarified that Differentiating the treatment strategies of triple-negative breast cancer and HER-2 positive breast cancer. The CRISPR/Cas9 system has provided a plethora of ideal methods to improve cell and animal models for studying the functions of genes and biological progresses; therefore, it has greatly promoted the study of various diseases in vitro and in vivo ( 28 ).…”

CRISPR: A new paradigm of theranostics

“…Mei et al (2020) have demonstrated the evolutionary relationships in breast cancer subtypes by developing a multiplexing CRISPR/dCas9 system. 86 Various applications of CRISPR-Cas system in cancer treatment have been shown in Figure 4 .

Figure 4 Therapeutic applications of CRISPR-Cas system in cancer.

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“… Breast cancer Breast cancer cells OCT4 , KLF , MYC , SOX2 Study the phylogenetic relationships among breast cancer subtypes as stratified by cancer stemness MCF7, SKBR3 and MDAMB231 Genome editing by overexpressing of OCT4 , KLF , MYC , SOX2 85 6. Colon organoids Human colonic stem cells mismatch repair gene MLH1 Explore the origin of cancer-associated mutational signatures MLH1 KO and NTHL1 KO Delete key DNA repair genes followed by delayed subcloning and whole-genome sequencing 86 …”