LHPP expression in triple-negative breast cancer promotes tumor growth and metastasis by modulating the tumor microenvironment
Year: 2025
Type: article
Abstract: Triple-negative breast cancer (TNBC) is a highly aggressive and metastatic form of breast cancer that lacks an effective targeted therapy. To identify new therapeutic targets, we investigated the phosphohistidine phosphatase, LHPP, which has been implicated in the development of several types of cancer. However, the full significance of LHPP in cancer progression remains unclear due to our limited understanding of its molecular mechanism. We found that levels of the LHPP phosphohistidine phosphatase were significantly increased in human breast cancer patients compared to normal adjacent tissues, with the highest levels in the TNBC subtype. When LHPP was knocked out in the MDA-MB-231 human TNBC cell line, cell proliferation, wound healing capacity, and invasion were significantly reduced. However, LHPP knockout in TNBC cells did not affect the phosphohistidine protein levels. Interestingly, LHPP knockout in MDA-MB-231 cells delayed tumor growth and reduced metastasis when orthotopically transplanted into mouse mammary glands. To investigate LHPP's role in breast cancer progression, we used next-generation sequencing and proximity-labeling proteomics, and found that LHPP regulates gene expression in chemokine-mediated signaling and actin cytoskeleton organization. Depletion of LHPP reduced the presence of tumor-infiltrating macrophages in mouse xenografts. Our results uncover a new tumor promoter role for LHPP phosphohistidine phosphatase in TNBC and suggest that targeting LHPP phosphatase could be a potential therapeutic strategy for TNBC.
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: hybrid
Funders: American Cancer Society, Pew Charitable Trusts, Salk Institute for Biological Studies, Moores Cancer Center, UC San Diego Health, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, National Institutes of Health, National Institute on Aging, National Cancer Institute
Awards: A Hybrid Quadrupole-Orbitrap LC/MS, San Diego Nathan Shock Center, G3239564077, American Cancer Society Institutional Research Grant, BD FACSAria Fusion for Flow Cytometry Core Facility, Combining single cell approaches and a developmental perspective to discover stem cell control circuits and the cellular and molecular bases of cancer heterogeneity, Specialized Cancer Center Support Grant, Modeling the tumor microenvironment of pancreatic ductal adenocarcinoma in next generation organoid models, Histidine phosphorylation as a new target for cancer therapy, Cancer Center Support Grant (CCSG)
OpenAlex ID: W4417002186