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Single cell sequencing identifies novel sub-populations of breast cancer cells selected under hypoxia

ABSTRACT: During tumour growth cancer cells are subject to and selected by microenvironmental stress. The selection of such cells allows for continued growth and survival, during hypoxia, acidosis, nutritional deprivation, drug treatment and radiation. However, there is great microenvironmental heterogeneity in every tumour. Must studies of gene regulation in vitro investigate whole cell populations, often by western blotting or mRNA expression. Thus, the individual variability of gene induction that could lead to selection, and basal cell molecular variability on which the selection operates, basic Darwinian principles, are not defined. We previously showed that two distinct populations can often be induced in epithelial tumour cell lines under hypoxia, identified by induction of Carbonic Anhydrase 9 [CA9].Here, we investigated the heterogeneity of breast cancer cells, and the relationship to the CA9 positive population in hypoxia, by using single cell sequencing analysis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE134038 | GEO | 2021/09/09

REPOSITORIES: GEO

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Project description:Breast cancer is a heterogeneous disease classified into 3 major subtypes based on the presence or absence of molecular markers for oestrogen receptors (ER), progesterone receptors (PR) and human epidermal growth factor-2 (Her2) . Hormone receptor-positive BC (ER+, PR+ and Her-2-), accounts for approximately 70% of patients. Patients with ER- BC account for approximately 30 % of all cases and commonly have a worse prognosis than ER+ patients (9). However, a significant proportion of ER- cases have good outcomes and could potentially benefit from a less aggressive therapy. Triple negative breast cancer (TNBC, ER-, PR- and Her-2-) accounts for approximately 15% of breast cancers and has the poorest outcomes. An hypoxic microenvironment is an important intrinsic component of solid tumours that can result in rapid proliferation of cancer cells and is associated with the lack of oxgyen and abnormal tumour blood vessels. Hypoxia stimulates the hypoxia inducible factor-1α (HIF-1α) that transactivates genes associated with angiogenesis, tumour growth, metastasis, metabolic reprogramming, and treatment resistance. HIF-1α is recognised to induce the expression of carbonic anhydrase IX (CAIX), an enzyme that has been attributed a central role in pH regulation and cancer progression and is particularly pronounced in peri necrotic tumour areas, high-grade BCs. The adaption to hypoxia is governed by multiple transcriptional and post-transcriptional changes in gene expression. Up to 1.5 % of the human genome is estimated to be transcriptionally responsive to hypoxia. Genes and pathways which have been identified as being responsive to hypoxia may have the potential to be used as prognostic or predictive markers, and furthermore, can help identify novel therapeutic targets. The aim of the present study was to gain a better understanding of the transcriptomic and protein pathways associated with CAIX in ER- BC to identify potential therapeutic targets against this aggressive phenotype.

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Single cell sequencing identifies novel sub-populations of breast cancer cells selected under hypoxia

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