Targeting arginine metabolism reverses bone immunosuppressive microenvironment and metastasis in ARID1A-deficient triple negative breast cancer
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Published on: September 26, 2016
Shuangyue Pan1,2, Jinyan Wang1,2, Boya Wang1,2
1Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.
Abstract:
Bone metastasis is a lethal consequence of breast cancer. AT-rich interaction domain 1 A gene (ARID1A), a subunit of the switch/sucrose non-fermentable (SWI/SNF) complex, regulates immunosuppressive tumor microenvironment. However, its specific role in bone metastasis remains unclear. Here, we show that female patients with ARID1A‑mutated triple negative breast cancer (TNBC) exhibit a higher bone metastasis incidence. Most ARID1A mutations result in loss of protein expression. ARID1A deficiency upregulates the arginine metabolic pathway, increasing ornithine and spermine levels that promote the expansion of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) within the bone marrow, thereby facilitating bone metastasis. Targeting key enzymes of arginase 2 (ARG2) and ornithine decarboxylase 1 (ODC1) in arginine metabolic pathway effectively reduces bone metastasis in ARID1A-deficient models. Collectively, these findings reveal that ARID1A deficiency promotes bone metastasis by activating arginine metabolism to expand PMN-MDSCs and potentially offers therapeutic strategies for preventing bone metastasis in female patients with ARID1A-deficient TNBC.
Insights
ARID1A gene mutations in triple-negative breast cancer promote bone metastasis by altering arginine metabolism and expanding immune-suppressing cells. Targeting ARG2 and ODC1 may prevent metastasis in patients with ARID1A-deficient tumors.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Bone metastasis is a major cause of death in breast cancer patients.
- The AT-rich interaction domain 1A (ARID1A) gene, part of the SWI/SNF complex, influences the tumor microenvironment.
- The specific role of ARID1A in bone metastasis is not well understood.
Purpose of the Study:
- To investigate the role of ARID1A in breast cancer bone metastasis.
- To elucidate the molecular mechanisms by which ARID1A deficiency affects bone metastasis.
- To identify potential therapeutic targets for ARID1A-mutated triple-negative breast cancer (TNBC).
Main Methods:
- Analysis of ARID1A mutation status and bone metastasis incidence in female TNBC patients.
- Investigation of ARID1A protein expression in relation to mutations.
- Assessment of arginine metabolic pathway alterations, including ornithine and spermine levels.
- Evaluation of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) expansion.
- In vivo studies targeting arginase 2 (ARG2) and ornithine decarboxylase 1 (ODC1) in ARID1A-deficient models.
Main Results:
- Female TNBC patients with ARID1A mutations show increased bone metastasis.
- ARID1A mutations often lead to loss of ARID1A protein expression.
- ARID1A deficiency upregulates arginine metabolism, increasing ornithine and spermine.
- Elevated metabolites promote PMN-MDSC expansion in the bone marrow, facilitating metastasis.
- Inhibition of ARG2 and ODC1 reduces bone metastasis in ARID1A-deficient models.
Conclusions:
- ARID1A deficiency promotes bone metastasis in TNBC by activating arginine metabolism and expanding PMN-MDSCs.
- Targeting ARG2 and ODC1 presents a potential therapeutic strategy for preventing bone metastasis in ARID1A-deficient TNBC.
- These findings highlight the critical role of ARID1A in regulating the bone metastatic process.
