ArticleBreast cancer research : BCR2014
Overcoming endocrine resistance due to reduced PTEN levels in estrogen receptor-positive breast cancer by co-targeting mammalian target of rapamycin, protein kinase B, or mitogen-activated protein kinase kinase.
Article in Breast cancer research : BCR, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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48 citing papers in PubMed, 70 citations in OpenAlex.
- Biomarkers of response to neoadjuvant palbociclib plus anastrozole in endocrine-resistant estrogen receptor-positive/HER2-negative breast cancer: a phase 2 trial.Nature communications · 2026Trial
- Low PTEN levels and PIK3CA mutations predict resistance to neoadjuvant lapatinib and trastuzumab without chemotherapy in patients with HER2 over-expressing breast cancer.Breast cancer research and treatment · 2018Trial
- Pictilisib for oestrogen receptor-positive, aromatase inhibitor-resistant, advanced or metastatic breast cancer (FERGI): a randomised, double-blind, placebo-controlled, phase 2 trial.The Lancet. Oncology · 2016Trial
- Quinazolinedione Derivatives as Potential Anticancer Agents Through Apoptosis Induction in MCF-7.International journal of molecular sciences · 2025Article
- Inhibition of NR2F2 restores hormone therapy response to endocrine refractory breast cancers.Science translational medicine · 2025Article
- SMAD4 depletion contributes to endocrine resistance by integrating ER and ERBB signaling in HR + HER2- breast cancer.Cell death & disease · 2024Article
- The intersection of the HER2-low subtype with endocrine resistance: the role of interconnected signaling pathways.Frontiers in oncology · 2024Article
- Overview of the therapeutic strategies for ER positive breast cancer.Biochemical pharmacology · 2023Review
- HER2-Positive Metastatic Breast Cancer: Available Treatments and Current Developments.Cancers · 2023Review
- Current Molecular Combination Therapies Used for the Treatment of Breast Cancer.International journal of molecular sciences · 2022Review
- Transcriptional coactivator MED1 in the interface of anti-estrogen and anti-HER2 therapeutic resistance.Cancer drug resistance (Alhambra, Calif.) · 2022Review
- Selective AKT kinase inhibitor capivasertib in combination with fulvestrant in PTEN-mutant ER-positive metastatic breast cancer.NPJ breast cancer · 2021Article
- Treatment of Luminal Metastatic Breast Cancer beyond CDK4/6 Inhibition: Is There a Standard of Care in Clinical Practice?Breast care (Basel, Switzerland) · 2021Review
- The 3D genomic landscape of differential response to EGFR/HER2 inhibition in endocrine-resistant breast cancer cells.Biochimica et biophysica acta. Gene regulatory mechanisms · 2020Article
- LncRNA AY343892 inhibits breast cancer development by positively regulating BRCA1-mediated transcription of PTEN.Histology and histopathology · 2020Article
- CXCR4 Antagonist AMD3100 Reverses the Resistance to Tamoxifen in Breast Cancer via Inhibiting AKT Phosphorylation.Molecular therapy oncolytics · 2020Article
- PTEN suppresses epithelial-mesenchymal transition and cancer stem cell activity by downregulating Abi1.Scientific reports · 2020Article
- Association of Abl interactor 2, ABI2, with platelet/lymphocyte ratio in patients with renal cell carcinoma: A pilot study.International journal of experimental pathology · 2020Article
- Overcoming Endocrine Resistance in Breast Cancer.Cancer cell · 2020Review
- Estrogen-induced transcription at individual alleles is independent of receptor level and active conformation but can be modulated by coactivators activity.Nucleic acids research · 2020Article
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30 authors at 6 institutions in 3 countries.
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Abstract
introductionActivation of the phosphatidylinositol 3-kinase (PI3K) pathway in estrogen receptor α (ER)-positive breast cancer is associated with reduced ER expression and activity, luminal B subtype, and poor outcome. Phosphatase and tensin homolog (PTEN), a negative regulator of this pathway, is typically lost in ER-negative breast cancer. We set out to clarify the role of reduced PTEN levels in endocrine resistance, and to explore the combination of newly developed PI3K downstream kinase inhibitors to overcome this resistance.
methodsAltered cellular signaling, gene expression, and endocrine sensitivity were determined in inducible PTEN-knockdown ER-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer cell and/or xenograft models. Single or two-agent combinations of kinase inhibitors were examined to improve endocrine therapy.
resultsModerate PTEN reduction was sufficient to enhance PI3K signaling, generate a gene signature associated with the luminal B subtype of breast cancer, and cause endocrine resistance in vitro and in vivo. The mammalian target of rapamycin (mTOR), protein kinase B (AKT), or mitogen-activated protein kinase kinase (MEK) inhibitors, alone or in combination, improved endocrine therapy, but the efficacy varied by PTEN levels, type of endocrine therapy, and the specific inhibitor(s). A single-agent AKT inhibitor combined with fulvestrant conferred superior efficacy in overcoming resistance, inducing apoptosis and tumor regression.
conclusionsModerate reduction in PTEN, without complete loss, can activate the PI3K pathway to cause endocrine resistance in ER-positive breast cancer, which can be overcome by combining endocrine therapy with inhibitors of the PI3K pathway. Our data suggests that the ER degrader fulvestrant, to block both ligand-dependent and -independent ER signaling, combined with an AKT inhibitor is an effective strategy to test in patients.
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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.