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Malignancy of breast cancer cells is increased in a luminal-hybrid state defined by progenitor markers CD146 and keratin 14

We first analyzed a patient-derived xenograft (PDX)-derived breast cancer cell line by dividing cell populations based on CD146-expression by FACS and found that this marker defines a cellular state with increased expression of a selection of luminal hybrid markers, including KRT14. We then knocked out CD146 or KRT14 in another patient-derived xenograft (PDX)-derived breast cancer cell line to investigate further the role of these markers in the hybrid state. For all these populations, we studied their gene expression by bulk RNA sequencing.

Type: RNASeq
Archive: European Genome-phenome Archive (EGA)

1 Dataset

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Dataset ID	Description	Technology	Samples
EGAD50000002857	Background: We have previously identified a subset of early human breast epithelial progenitors that, despite their luminal affiliation, are enriched for basal markers, including CD146 and keratin 14 (K14). This simultaneous presence of both lineages thus defines a luminal-hybrid state. As luminal progenitors are generally proposed as a cell of origin of breast carcinoma, we examined how cells within this luminal hybrid state relate to breast cancer malignancy. Findings: We first analyzed two patient-derived xenograft (PDX)-derived breast cancer cell lines by dividing cell populations based on CD146-expression by FACS and found that this marker defines a cellular state with increased expression of a selection of luminal hybrid markers, including KRT14. When subjecting the sorted cells to in vitro transwell filter analysis, CD146HI/K14HI luminal hybrid state cells were less invasive. Knocking out either CD146- or K14-expression by CRISPR/Cas9 on a CD146/K14-positive background did not affect the in vivo tumorigenic potential, nor the differentiation state. However, when subjecting the respective sorted populations to a soft agar colony formation assay or as in vivo xenografts, CD146HI/K14HI cells exhibited more growth and metastasis, suggesting that the luminal hybrid state contributes to malignant properties. Conclusions: Our findings demonstrate that multiple components of the luminal hybrid state provide distinct properties to tumor malignancy. The fact that breast cancer can reflect a significant part of the original breast gland differentiation hierarchy may add weight to the argument that the search for novel strategies for treating basal-like breast cancer should include manipulation of cellular differentiation states.	unspecified	12