ArticleClinical & experimental metastasis2014
Wnt signaling induces gene expression of factors associated with bone destruction in lung and breast cancer.
Article in Clinical & experimental metastasis, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed.
- A Computational Model of Tumor Interactions with Bone-Resident Cells Predicts Tumor-Type-Specific Responses to Perturbations.bioRxiv : the preprint server for biology · 2026Article
- Research Progress on Signaling Pathways in Breast Cancer Bone Metastasis.Oncology research · 2026Review
- PTHrP buffers Wnt/β-catenin activity through a PKC-ζ involved negative feedback loop to maintain articular cartilage homeostasis and attenuate osteoarthritis.Journal of orthopaedic translation · 2025Article
- Role of the Wnt signaling pathway in the complex microenvironment of breast cancer and prospects for therapeutic potential (Review).International journal of oncology · 2025Review
- Pharmacologic Hedgehog inhibition modulates the cytokine profile of osteolytic breast cancer cells.Journal of bone oncology · 2024Article
- Article
- Sclerostin blockade promotes bone metastases of Wnt-responsive breast cancer cells.Cancer science · 2023Article
- Parathyroid Hormone-Related Protein/Parathyroid Hormone Receptor 1 Signaling in Cancer and Metastasis.Cancers · 2023Review
- Review
- Tumor microenvironment involvement in colorectal cancer progressionWorld journal of gastroenterology · 2022Review
- Beyond Genetics: Metastasis as an Adaptive Response in Breast Cancer.International journal of molecular sciences · 2022Review
- Article
- Correlation between targeted RNAseq signature of breast cancer CTCs and onset of bone-only metastases.British journal of cancer · 2022Article
- Advancing Treatment of Bone Metastases through Novel Translational Approaches Targeting the Bone Microenvironment.Cancers · 2022Review
- MicroRNA-106a regulates autophagy-related cell death and EMT by targeting TP53INP1 in lung cancer with bone metastasis.Cell death & disease · 2021Article
- The Role of Smoothened-Dependent and -Independent Hedgehog Signaling Pathway in Tumorigenesis.Biomedicines · 2021Review
- Targeting Histone Modifications in Bone and Lung Metastatic Cancers.Current osteoporosis reports · 2021Review
- From Good to Bad: The Opposing Effects of PTHrP on Tumor Growth, Dormancy, and Metastasis Throughout Cancer Progression.Frontiers in oncology · 2021Review
- Hypoxia in bone metastasis and osteolysis.Cancer letters · 2020Review
- Article
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6 authors.
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Abstract
Parathyroid hormone-related protein (PTHrP) is an important regulator of bone destruction in bone metastatic tumors. Transforming growth factor-beta (TGF-β) stimulates PTHrP production in part through the transcription factor Gli2, which is regulated independent of the Hedgehog signaling pathway in osteolytic cancer cells. However, inhibition of TGF-β in vivo does not fully inhibit tumor growth in bone or tumor-induced bone destruction, suggesting other pathways are involved. While Wnt signaling regulates Gli2 in development, the role of Wnt signaling in bone metastasis is unknown. Therefore, we investigated whether Wnt signaling regulates Gli2 expression in tumor cells that induce bone destruction. We report here that Wnt activation by β-catenin/T cell factor 4 (TCF4) over-expression or lithium chloride (LiCl) treatment increased Gli2 and PTHrP expression in osteolytic cancer cells. This was mediated through the TCF and Smad binding sites within the Gli2 promoter as determined by promoter mutation studies, suggesting cross-talk between TGF-β and Wnt signaling. Culture of tumor cells on substrates with bone-like rigidity increased Gli2 and PTHrP production, enhanced autocrine Wnt activity and led to an increase in the TCF/Wnt signaling reporter (TOPFlash), enriched β-catenin nuclear accumulation, and elevated Wnt-related genes by PCR-array. Stromal cells serve as an additional paracrine source of Wnt ligands and enhanced Gli2 and PTHrP mRNA levels in MDA-MB-231 and RWGT2 cells in vitro and promoted tumor-induced bone destruction in vivo in a β-catenin/Wnt3a-dependent mechanism. These data indicate that a combination of matrix rigidity and stromal-secreted factors stimulate Gli2 and PTHrP through Wnt signaling in osteolytic breast cancer cells, and there is significant cross-talk between the Wnt and TGF-β signaling pathways. This suggests that the Wnt signaling pathway may be a potential therapeutic target for inhibiting tumor cell response to the bone microenvironment and at the very least should be considered in clinical regimens targeting TGF-β signaling.
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