ArticleCancer research communications2024
WNT4 Regulates Cellular Metabolism via Intracellular Activity at the Mitochondria in Breast and Gynecologic Cancers.
Article in Cancer research communications, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 9 citations in OpenAlex.
- Models of high-grade serous carcinoma of tubo-ovarian origin.Oncology reviews · 2026Review
- Unlocking the mitochondrial functional code: unraveling the pathogenesis of ovarian cancer and innovative targets to inhibit malignant behavior.Journal of translational medicine · 2025Review
- Co-targeting of metabolism using dietary and pharmacologic approaches reduces breast cancer metastatic burden.NPJ breast cancer · 2025Article
- Differential Gene Expression Analysis in a Lumbar Spinal Stenosis Rat Model via RNA Sequencing: Identification of Key Molecular Pathways and Therapeutic Insights.Biomedicines · 2025Article
- A Stronger IMPACT on Career Development for Early- and Mid-career Faculty.Journal of the Endocrine Society · 2024Article
- Glutamate Transport Proteins and Metabolic Enzymes are Poor Prognostic Factors in Invasive Lobular Carcinoma.bioRxiv : the preprint server for biology · 2024Article
- Claudin-4 remodeling of nucleus-cell cycle crosstalk maintains ovarian tumor genome stability and drives resistance to genomic instability-inducing agents.bioRxiv : the preprint server for biology · 2024Article
- A Path to Precision Metabolic Treatment in Breast Cancer: Riluzole, Glutamate Signaling, and Invasive Lobular Carcinoma.Journal of the Endocrine Society · 2024Article
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Authors and funding
14 authors at 7 institutions in 1 country.
Funding
Abstract
Wnt ligand WNT4 is critical in female reproductive tissue development, with WNT4 dysregulation linked to related pathologies including breast cancer (invasive lobular carcinoma, ILC) and gynecologic cancers. WNT4 signaling in these contexts is distinct from canonical Wnt signaling yet inadequately understood. We previously identified atypical intracellular activity of WNT4 (independent of Wnt secretion) regulating mitochondrial function, and herein examine intracellular functions of WNT4. We further examine how convergent mechanisms of WNT4 dysregulation impact cancer metabolism. In ILC, WNT4 is co-opted by estrogen receptor α (ER) via genomic binding in WNT4 intron 1, while in gynecologic cancers, a common genetic polymorphism (rs3820282) at this ER binding site alters WNT4 regulation. Using proximity biotinylation (BioID), we show canonical Wnt ligand WNT3A is trafficked for secretion, but WNT4 is localized to the cytosol and mitochondria. We identified DHRS2, mTOR, and STAT1 as putative WNT4 cytosolic/mitochondrial signaling partners. Whole metabolite profiling, and integrated transcriptomic data, support that WNT4 mediates metabolic reprogramming via fatty acid and amino acid metabolism. Furthermore, ovarian cancer cell lines with rs3820282 variant genotype are WNT4 dependent and have active WNT4 metabolic signaling. In protein array analyses of a cohort of 103 human gynecologic tumors enriched for patient diversity, germline rs3820282 genotype is associated with metabolic remodeling. Variant genotype tumors show increased AMPK activation and downstream signaling, with the highest AMPK signaling activity in variant genotype tumors from non-White patients. Taken together, atypical intracellular WNT4 signaling, in part via genetic dysregulation, regulates the distinct metabolic phenotypes of ILC and gynecologic cancers. SIGNIFICANCE: WNT4 regulates breast and gynecologic cancer metabolism via a previously unappreciated intracellular signaling mechanism at the mitochondria, with WNT4 mediating metabolic remodeling. Understanding WNT4 dysregulation by estrogen and genetic polymorphism offers new opportunities for defining tumor biology, precision therapeutics, and personalized cancer risk assessment.
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