ArticleCancer research2011
TGF-beta promotion of Gli2-induced expression of parathyroid hormone-related protein, an important osteolytic factor in bone metastasis, is independent of canonical Hedgehog signaling.
Article in Cancer research, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 127 papers.
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Who cites it
127 citing papers in PubMed, 197 citations in OpenAlex.
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- Malignancy-Associated Hypercalcemia and Kidney Disease: Facts, Controversies, and Management.Kidney medicine · 2026Review
- Perineal Verrucous Carcinoma Associated With Hypercalcemia: First Clinical Report of Parathyroid Hormone-Related Protein-producing Tumor.Plastic and reconstructive surgery. Global open · 2026Article
- Acute toxicological evaluation of bone-targeted parathyroid hormone-related peptide (PTHrP) antagonist to inhibit breast cancer metastases to bone.Toxicology reports · 2025Article
- Estrogen Receptors as Key Factors in Carcinogenesis.Biomedicines · 2025Review
- 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
- Cutaneous Squamous Cell Carcinoma Producing Granulocyte Colony-stimulating Factor and Parathyroid Hormone-related Protein: A Case Report and Literature Review.Internal medicine (Tokyo, Japan) · 2025Review
- Role of EMT in drug resistance of breast cancer: molecular mechanisms and therapeutic strategies.Frontiers in oncology · 2025Review
- Prostate Cancer Bone Metastasis: Molecular Mechanisms of Tumor and Bone Microenvironment.Cancer management and research · 2025Review
- Interactions between hedgehog signaling pathway and the complex tumor microenvironment in breast cancer: current knowledge and therapeutic promises.Cell communication and signaling : CCS · 2024Review
- Pharmacologic Hedgehog inhibition modulates the cytokine profile of osteolytic breast cancer cells.Journal of bone oncology · 2024Article
- PTHrP intracrine actions divergently influence breast cancer growth through p27 and LIFR.Breast cancer research : BCR · 2024Article
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- Targeting transforming growth factor beta signaling in metastatic osteosarcoma.Journal of bone oncology · 2023Review
- PIK3CD correlates with prognosis, epithelial-mesenchymal transition and tumor immune infiltration in breast carcinoma.Discover oncology · 2023Article
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- Hedgehog signaling regulates bone homeostasis through orchestrating osteoclast differentiation and osteoclast-osteoblast coupling.Cellular and molecular life sciences : CMLS · 2023Article
- How has the field of metastatic breast cancer in bones evolved over the past 22 years?Journal of bone oncology · 2023Article
- Parathyroid Hormone-Related Protein/Parathyroid Hormone Receptor 1 Signaling in Cancer and Metastasis.Cancers · 2023Review
- Select HDAC Inhibitors Enhance Osteolysis and Bone Metastasis Outgrowth but Can Be Mitigated With Bisphosphonate Therapy.JBMR plus · 2023Article
67 more citing papers are in PubMed but not listed here.
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
Abstract
Breast cancer frequently metastasizes to bone, in which tumor cells receive signals from the bone marrow microenvironment. One relevant factor is TGF-β, which upregulates expression of the Hedgehog (Hh) signaling molecule, Gli2, which in turn increases secretion of important osteolytic factors such as parathyroid hormone-related protein (PTHrP). PTHrP inhibition can prevent tumor-induced bone destruction, whereas Gli2 overexpression in tumor cells can promote osteolysis. In this study, we tested the hypothesis that Hh inhibition in bone metastatic breast cancer would decrease PTHrP expression and therefore osteolytic bone destruction. However, when mice engrafted with human MDA-MB-231 breast cancer cells were treated with the Hh receptor antagonist cyclopamine, we observed no effect on tumor burden or bone destruction. In vitro analyses revealed that osteolytic tumor cells lack expression of the Hh receptor, Smoothened, suggesting an Hh-independent mechanism of Gli2 regulation. Blocking Gli signaling in metastatic breast cancer cells with a Gli2-repressor gene (Gli2-rep) reduced endogenous and TGF-β-stimulated PTHrP mRNA expression, but did not alter tumor cell proliferation. Furthermore, mice inoculated with Gli2-Rep-expressing cells exhibited a decrease in osteolysis, suggesting that Gli2 inhibition may block TGF-β propagation of a vicious osteolytic cycle in this MDA-MB-231 model of bone metastasis. Accordingly, in the absence of TGF-β signaling, Gli2 expression was downregulated in cells, whereas enforced overexpression of Gli2 restored PTHrP activity. Taken together, our findings suggest that Gli2 is required for TGF-β to stimulate PTHrP expression and that blocking Hh-independent Gli2 activity will inhibit tumor-induced bone destruction.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.