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Molecular characterization of a toxicological tipping point in human induced pluripotent stem cell (hiPSC)-derived endoderm exposed to all-trans retinoic acid (ATRA)

ABSTRACT: Molecular characterization of a toxicological tipping point in human induced pluripotent stem cell (hiPSC)-derived endoderm exposed to all-trans retinoic acid (ATRA)

PROVIDER: PRJNA545324 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR9153260.fastq.gz	Fastqsanger.gz
	SRR9153270.fastq.gz	Fastqsanger.gz
	SRR9153280.fastq.gz	Fastqsanger.gz
	SRR9153290.fastq.gz	Fastqsanger.gz
	SRR9153261.fastq.gz	Fastqsanger.gz

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Project description:Retinoids have been used as potential chemotherapeutic or chemo-preventive agents because of their differentiation, anti-proliferative, pro-apoptotic, and anti-oxidant effects. We investigated the effect of all trans- retinoic acid (ATRA) at different stages of the neoplastic transformation using an in vitro model of breast cancer progression. This model was previously developed by treating the human normal-like breast epithelial MCF-10F cells with high dose of estradiol and consist of five cell lines which shown a progressive neoplastic transformation: MCF-10F (normal stage), trMCF (premalignant stage), bsMCF (invasive stage) and caMCF (tumorigenic stage). In 3D-cultures, MCF-10F cells form tubules resembling the normal mammary gland although after treatment with high doses of estradiol, trMCF cells, formed tubules and, spherical masses which are an indication of cell transformation. By ring cloning, trMCF clone 11 which only formed spherical masses in collagen was isolated. Our results showed that the early transformed trMCF clone 11 cells shown a reduction of spherical masses and increased of tubules in collagen after being treated with 10-5M (10µM) and 10-6M (1µM) ATRA; the number of tubules was higher in cells treated with 10-6M ATRA (43% vs. 10% tubules). The invasive bsMCF and tumorigenic caMCF cells did not shown any changes in morphology after ATRA treatment. Analysis of expression studies in early transformed cells treated with 10-6M ATRA showed that 271 probes upregulated in trMCF clone 11 cells were downregulated after ATRA treatment and, 316 probes that were downregulated were upregulated after ATRA treatment in these cells to similar levels than the normal breast epithelial cells MCF-10F. These genes were involved in the aryl hydrocarbon receptor signaling, RAR Activation, xenobiotic metabolisms signaling, molecular mechanisms of cancer and cell morphology. Our results shown that ATRA was able to re-differentiate transformed cells at early stages of the neoplastic process suggesting that ATRA could potentially be used to inhibit the progression of premalignant lesions of the breast such as ductal carcinoma in situ (DCIS).

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Molecular characterization of a toxicological tipping point in human induced pluripotent stem cell (hiPSC)-derived endoderm exposed to all-trans retinoic acid (ATRA)

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