MassIVE MSV000096128

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Multi-omics integration reveals silencing of Arginosuccinate synthase and upregulation of nucleotide biosynthesis in tamoxifen resistant invasive lobular carcinoma

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Description

Invasive Lobular Carcinoma (ILC), a distinct subtype of breast cancer is hallmarked by E-Cadherin loss, slow proliferation, and hormone receptor positivity. Major challenges in clinical management of ILC is advanced stage at diagnosis, resistance to endocrine therapy, a cornerstone in treating ILC patients, and late recurrence. To elucidate the mechanisms underlying endocrine resistance in ILC, we have generated ILC cell lines (MDA-MB-134-VI and SUM44PE) resistant to tamoxifen, a selective estrogen receptor modulator. Our study reveals methylation mediated silencing of ASS1 and demethylation restored ASS1 expression markedly reducing IC50 for tamoxifen. Treating TAMR cell with Decitabine, a demethylating agent, or Farudodstat, a pyrimidine biosynthesis inhibitor, markedly augmented efficacy of tamoxifen. Collectively, our study unveils ASS1 downregulation as a novel mechanism underlying acquired resistance to tamoxifen in ILC and establishes a metabolic link between ASS1 and nucleic acid biosynthesis. ASS1 can be a potential biomarker and a therapeutic target in tamoxifen resistant ILC patients, warranting further investigation. [doi:10.25345/C57P8TR4B] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: ILC ; drug resistance ; Tamoxifen ; metabolomics ; multi-omics ; DatasetType:Metabolomics

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Principal Investigators:
(in alphabetical order) 		Jiangjiang Zhu, Ohio State University, USA
Submitting User: choueiry_2
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