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Gene expression of clinical breast cancer cells cultured by sphere and adherent culture methods

ABSTRACT: Cancer stem-like cells (CSCs) are thought to be responsible for recurrence of tumors and poor prognosis because of their higher tumor initiating ability and drug resistance, though the mechanisms remain still unclear. Here, we show a critical role of mini-chromosome maintenance protein (MCM) 10, a component of DNA replication machinery, in enabling CSCs to deal with DNA replicative stress. Our transcriptomic analysis of patient-derived cultured breast cancer cells revealed that MCM10 is strongly upregulated in CSC-enriched spheroid cells, compared to cancer cells cultured in a regular condition. Elevated MCM10 expression was correlated with worse prognosis of patients with breast cancer. Depletion of MCM10 resulted in not only reduced cell proliferation and tumorigenesis, but also reduced tumor sphere forming efficiency, expression levels of stemness markers, and the tumor initiating ability. These results indicate that MCM10 is essential for maintenance of CSCs as well as for tumor cell proliferation. DNA fiber assay revealed that CSCs have a comparatively high level of DNA replicative stress. Overexpression of MCM10 helped cells to proliferate in a medium containing hydroxyurea (HU), a replicative stress-inducing chemotherapeutic agent. Conversely, MCM10 depletion made cells more fragile to replicative stress induced by HU or mitomycin C (MMC), another replicative stress inducer. Therefore, MCM10 plays critical roles for dealing with the enhanced replicative stress generated in CSCs for their survival, leading to maintenance of tumor initiating ability and drug resistance. We provide a preclinical rationale to target MCM10, the critical mediator for DNA replicative stress, for breast cancer that includes CSCs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE127264 | GEO | 2021/09/09

REPOSITORIES: GEO

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Project description:Aberrant cell proliferation, a hallmark of most cancers, requires the escape from intrinsic antitumour barriers. Primary among these is the DNA damage response (DDR). In both cell culture-models and in early stages of tumorigenesis in vivo, activated oncogenes induce DNA replication stress and DNA double-strand breaks (DSBs), leading to DDR activation and p53-dependent apoptosis and/or senescence. The means by which tumour initiating cells, also termed cancer stem cells (CSCs), circumvent this oncosuppressive response is unknown. Here we demonstrate that the ZEB1 transcription factor provides breast CSCs with the ability to withstand an aberrant mitogenic activity. Its forced expression in human mammary epithelial cells is sufficient to alleviate DNA replicative stress and to decrease the production of reactive oxygen species, an important contributor to DDR and oncogene-induced senescence. Consistently, human breast cancer cells with endogenous ZEB1 expression show two characteristic features: low levels of DSBs and DDR markers, reflecting mitigation of the DNA replication stress, and a low p53 mutation frequency, reflecting a weak selective pressure for inactivation. Using high-throughput sequencing analysis of controlled cellular models, we further demonstrate that ZEB1 delays the onset of structural chromosomal instability (CIN), a known consequence of replicative stress and prevents the emergence of chromosome 8p deletions and 8q amplifications, two prevalent abnormalities in high grade breast cancers. Supporting these findings, ZEB1 expression discriminates human breast tumours by their copy number alterations (CNAs) and chromosome 8 aberrations. We propose that the tumorigenic potential of CSCs relies upon their unique capacity to tolerate oncogenic stimuli through the alleviation of DNA replication stress. Immortalized human mammary epithelial cells were infected with retrovirus expressing H-RASV12 with or without a retrovirus expressing ZEB1.

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Gene expression of clinical breast cancer cells cultured by sphere and adherent culture methods

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