ArticleCancer research2012
Hedgehog signaling is a novel therapeutic target in tamoxifen-resistant breast cancer aberrantly activated by PI3K/AKT pathway.
Article in Cancer research, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 125 papers, 1 of them a synthesis that pooled it.
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Who cites it
125 citing papers in PubMed, 1 synthesis or guideline pooled it, 190 citations in OpenAlex.
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- Non-coding RNA-mediated mechanisms underlying tamoxifen resistance in breast cancer.Discover oncology · 2026Review
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- Protein Marker-Dependent Drug Discovery Targeting Breast Cancer Stem Cells.International journal of molecular sciences · 2025Review
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- CLDN11 deficiency upregulates FOXM1 to facilitate breast tumor progression through hedgehog signaling pathway.Journal of molecular histology · 2024Article
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- Advances in the Understanding of the Pathogenesis of Triple-Negative Breast Cancer.Cancer medicine · 2024Review
- Interactions between hedgehog signaling pathway and the complex tumor microenvironment in breast cancer: current knowledge and therapeutic promises.Cell communication and signaling : CCS · 2024Review
- Mitogen signaling strength and duration can control cell cycle decisions.Science advances · 2024Review
- Positive correlation between the nuclear expression of GPER and pGLI3 in prostate cancer tissues from patients with different Gleason scores.Frontiers in endocrinology · 2024Article
- Therapeutic vulnerabilities of cancer stem cells and effects of natural products.Natural product reports · 2023Review
- CAFs-derived SCUBE1 promotes malignancy and stemness through the Shh/Gli1 pathway in hepatocellular carcinoma.Journal of translational medicine · 2022Article
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- The ELEANOR noncoding RNA expression contributes to cancer dormancy and predicts late recurrence of estrogen receptor-positive breast cancer.Cancer science · 2022Article
- Cancer-associated fibroblasts in breast cancer: Challenges and opportunities.Cancer communications (London, England) · 2022Review
- Single-Cell Profiling of Tumor Microenvironment Heterogeneity in Osteosarcoma Identifies a Highly Invasive Subcluster for Predicting Prognosis.Frontiers in oncology · 2022Article
- Breast Cancer Stem-Like Cells in Drug Resistance: A Review of Mechanisms and Novel Therapeutic Strategies to Overcome Drug Resistance.Frontiers in oncology · 2022Review
65 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
Endocrine resistance is a major challenge in the management of estrogen receptor (ER)-positive breast cancers. Although multiple mechanisms leading to endocrine resistance have been proposed, the poor outcome of patients developing resistance to endocrine therapy warrants additional studies. Here we show that noncanonical Hedgehog (Hh) signaling is an alternative growth promoting mechanism that is activated in tamoxifen-resistant tumors. Importantly, phosphoinositide 3-kinase inhibitor/protein kinase B (PI3K/AKT) pathway plays a key role in regulating Hh signaling by protecting key components of this pathway from proteasomal degradation. The levels of Hh-signaling molecules SMO and GLI1 and the targets were significantly elevated in tamoxifen-resistant MCF-7 cells and T47D cells. Serial passage of the resistant cells in mice resulted in aggressive tumors that metastasized to distant organs with concurrent increases in Hh marker expression and epithelial mesenchymal transition. RNAi-mediated depletion of SMO or GLI1 in the resistant cells resulted in reduced proliferation, clonogenic survival and delayed G(1)-S transition. Notably, treatment of resistant cells with PI3K inhibitors decreased SMO and GLI1 protein levels and activity that was rescued upon blocking GSK3β and proteasomal degradation. Furthermore, treatment of tamoxifen-resistant xenografts with anti-Hh compound GDC-0449 blocked tumor growth in mice. Importantly, high GLI1 expression correlated inversely with disease-free and overall survival in a cohort of 315 patients with breast cancer. In summary, our results describe a signaling event linking PI3K/AKT pathway with Hh signaling that promotes tamoxifen resistance. Targeting Hh pathway alone or in combination with PI3K/AKT pathway could therefore be a novel therapeutic option in treating endocrine-resistant breast cancer.
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Registered trials
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.