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

ABSTRACT: 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.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Invasive Lobular Carcinoma

SUBMITTER: Jiangjiang Zhu

PROVIDER: MSV000096128 | MassIVE | Fri Oct 18 09:14:00 BST 2024

REPOSITORIES: MassIVE

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Project description:MCM3 is one of several genes whose expression profile is markedly altered in tamoxifen-resistant breast cancer cell lines. We observed that increased MCM3 expression is associated with tamoxifen resistance. Knockdown of MCM3 resulted in increased susceptibility of tamoxifen-resistant breast cancer cell lines. Moreover, MCM3 expression is significantly associated with clinical outcome of endocrine treated receptor positive breast cancer. To understand the effect of MCM3 on the mechanism of endocrine resistance, we performed gene expression array on tamoxifen-resistant breast cancer cell lines. Here we show that MCM3 knockdown affects the expression of hundreds of genes. Resistance to endocrine therapy in estrogen receptor-positive (ER+) breast cancer is a major clinical problem with poorly understood mechanisms. There is an unmet need for prognostic and predictive biomarkers to allow appropriate therapeutic targeting. We evaluated the mechanism by which minichromosome maintenance protein 3 (MCM3) influences endocrine resistance and its predictive/prognostic potential in ER+ breast cancer. We discovered that ER+ breast cancer cells survive tamoxifen and letrozole treatments through upregulation of minichromosome maintenance proteins (MCMs), including MCM3, which are key molecules in cell cycle and DNA replication. Lowering MCM3 expression in endocrine-resistant cells restored drug sensitivity and altered phosphorylation of cell cycle regulators, including p53(Ser315,33), CHK1(Ser317) and cdc25b(Ser323), suggesting that the interaction of MCM3 with cell cycle proteins is an important mechanism of overcoming replicative stress and anti-proliferative effects of endocrine treatments. Evaluation of MCM3 levels in primary tumors from four independent cohorts of breast cancer patients receiving adjuvant tamoxifen mono-therapy or no adjuvant treatment, including the Stockholm tamoxifen (STO-3) trial, showed MCM3 to be an independent prognostic adding information beyond Ki67. In addition, MCM3 was shown to be a predictive marker of response to endocrine treatment. Our study reveals a coordinated signaling network centered around MCM3 that limits response to endocrine therapy in ER+ breast cancer and identifies MCM3 as a clinically useful prognostic and predictive biomarker that allows personalized treatment of ER+ breast cancer patients.

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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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