Low Methionine Diet Shows Promise in Eliminating Triple-Negative Breast Cancer Stem Cells

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Low Methionine Diet Shows Promise in Eliminating Triple-Negative Breast Cancer Stem Cells

Low Methionine Diet Shows Promise in Eliminating Triple-Negative Breast Cancer Stem Cells

Triple-negative breast cancer (TNBC) is characterized by its high biological malignancy, strong invasiveness, and poor prognosis, posing a significant challenge in clinical diagnosis and treatment.

Tumor stem cells, a small group of tumor cells with the ability to form tumors, self-renew, and exhibit low differentiation, play a crucial role in TNBC, contributing to treatment resistance, recurrence, and metastasis.

Targeting these tumor stem cells has emerged as a key strategy in the therapeutic approach for TNBC.

On January 29, 2024, Fudan University’s affiliated Cancer Hospital published a research report in the online edition of “Cell Reports Medicine,” revealing the role of the BRCA2-interacting transcriptional repressor EMSY in reshaping the tumor metabolic microenvironment and enhancing methionine metabolism.

The study, led by Dr. Liu Cuicui and the team of Dr. Yu Keda, demonstrated that manipulating methionine levels through diet could specifically eliminate TNBC stem cells, ultimately inhibiting tumor progression.

The research, which integrated multi-omics data analysis, cellular functional experiments, mouse models, and clinical sample validation from Fudan University’s affiliated Cancer Hospital TNBC cohort, identified several critical molecules that amplify the expression in TNBC tumor stem cell subpopulations, significantly affecting the enrichment of aldehyde dehydrogenase (a classic marker of breast cancer stem cells). Of particular interest was EMSY, which induced a phenotype resembling BRCA mutations and was found to be highly expressed in the TNBC stem cell population. Elevated EMSY levels promoted the enrichment of aldehyde dehydrogenase-positive cells, enhancing the self-renewal and tumor-forming ability of tumor stem cells, showing a significant positive correlation with adverse outcomes in TNBC patients.

Mechanistically, the study revealed that EMSY competitively binds to lysine-specific demethylase 5B (KDM5B, also known as histone demethylase JARID1B) JmjC domain, a crucial domain for KDM5B enzyme activity. EMSY inhibition of KDM5B enzyme activity regulated methionine metabolism and the level of trimethylation on the fourth lysine residue of histone H3 (H3K4me3), promoting self-renewal and tumor formation in breast cancer stem cells. Additionally, in TNBC patient-derived tumor xenograft models with amplified EMSY, a combination therapy of poly ADP-ribose polymerase (PARP) inhibitor Olaparib (especially effective for non-tumor stem cells) and methionine-deprived diet showed better efficacy in killing tumor cells, reducing breast cancer stem cell proportion, and inhibiting tumor growth.

Therefore, the study elucidates a novel molecular mechanism of EMSY-mediated methionine metabolism in regulating tumor stem cells and the progression of TNBC. The proposed combination therapy involving PARP inhibitor and methionine-deprived diet represents a promising strategy for TNBC treatment. Understanding the unique amino acid metabolism characteristics of tumor stem cells and targeting their vulnerabilities will become a crucial clinical approach for eradicating tumor stem cells, offering a new strategy in cancer treatment.

Low Methionine Diet Shows Promise in Eliminating Triple-Negative Breast Cancer Stem Cells

Controlling methionine intake can disrupt the normal methylation of tumors. Achieving a low methionine diet is not difficult, as high methionine content is primarily found in meat, eggs, and dairy products. Some low methionine (<100mg/100g) foods include: