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A stemness-related ZEB1-MSRB3 axis governs cellular pliancy and cancer genome stability.

ABSTRACT: Genomic instability is a prominent driver of tumorigenesis. However, a significant fraction of human cancers display few genomic aberrations, suggesting alternative roads towards malignancy. Here, we show that the differentiation status of normal human mammary epithelial cells influences the early response to an oncogenic activation and determines the genetic routes towards tumorigenesis. Following an oncogenic insult, luminal progenitors and differentiated luminal cells undergo oxidative and DNA replication stress, initiating genomic instability. In contrast, mammary stem cells exhibit the innate capacity to withstand aberrant mitogenic activation, fostering malignant transformation. This property relies upon a pre-emptive program driven by the ZEB1 transcription factor and the methionine sulfoxide reductase MSRB3. The ZEB1-MSRB3 axis governs cellular pliancy and prevents the continuous formation of oncogene-induced DNA damage, leading to neoplasms with unique pathological features. These gene expression data correspond to the different subpopulations that compose the hierarchy of normal human mammary epithelial cells. These subpopulations were freshly isolated from mammary tissue, originating from reduction mammoplasties and flow sorted using four markers (EpCAM, CD10, CD49f, ALDH). Three subpopulations enriched in mammary stem cells (MaSCs) are designed as MaSC1, 2, 3; the luminal progenitor are designed as LP, and the mature luminal cells as mL1 and mL2.

ORGANISM(S): Homo sapiens

SUBMITTER: Arnaud Vigneron

PROVIDER: E-MTAB-4145 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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