ArticleCancer research2009
Expression of the K303R estrogen receptor-alpha breast cancer mutation induces resistance to an aromatase inhibitor via addiction to the PI3K/Akt kinase pathway.
Article in Cancer research, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed, 71 citations in OpenAlex.
- Genomic landscape of hormone therapy-resistant HR-positive, HER2-negative breast cancer.Breast cancer research and treatment · 2025Article
- SYT7 promotes breast cancer cells growth through the PI3K/AKT pathway.Translational cancer research · 2024Article
- Estrogen Receptor Alpha Mutations, Truncations, Heterodimers, and Therapies.Endocrinology · 2024Review
- Autophagy and senescence facilitate the development of antiestrogen resistance in ER positive breast cancer.Frontiers in endocrinology · 2024Review
- A modular microfluidic platform to study how fluid shear stress alters estrogen receptor phenotype in ERMicrosystems & nanoengineering · 2024Article
- A modular microfluidic platform to study how fluid shear stress alters estrogen receptor phenotype in ERResearch square · 2023Article
- Advances in Endocrine Therapy for Hormone Receptor-Positive Advanced Breast Cancer.Current oncology reports · 2023Review
- Estrogen/HER2 receptor crosstalk in breast cancer: combination therapies to improve outcomes for patients with hormone receptor-positive/HER2-positive breast cancer.NPJ breast cancer · 2023Review
- Cell-free DNA analysis in current cancer clinical trials: a review.British journal of cancer · 2022Review
- Obesity and endocrine therapy resistance in breast cancer: Mechanistic insights and perspectives.Obesity reviews : an official journal of the International Association for the Study of Obesity · 2022Review
- Article
- Laboratory Models for Investigating Breast Cancer Therapy Resistance and Metastasis.Frontiers in oncology · 2021Review
- Review
- Leptin Signaling Contributes to Aromatase Inhibitor Resistant Breast Cancer Cell Growth and Activation of Macrophages.Biomolecules · 2020Article
- PIK3CA Mutational Status Is Associated with High Glycolytic Activity in ER+/HER2- Early Invasive Breast Cancer: a Molecular Imaging Study Using [Molecular imaging and biology · 2019Article
- Insights into how phosphorylation of estrogen receptor at serine 305 modulates tamoxifen activity in breast cancer.Molecular and cellular endocrinology · 2019Review
- Ethanol extract ofCancer cell international · 2019Article
- Candidate tumor suppressor gene IRF6 is involved in human breast cancer pathogenesis via modulating PI3K-regulatory subunit PIK3R2 expression.Cancer management and research · 2019Article
- Comprehensive Profiling of DNA Repair Defects in Breast Cancer Identifies a Novel Class of Endocrine Therapy Resistance Drivers.Clinical cancer research : an official journal of the American Association for Cancer Research · 2018Article
- The Impact of ESR1 Mutations on the Treatment of Metastatic Breast Cancer.Hormones & cancer · 2018Review
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Authors and funding
9 authors at 4 institutions in 4 countries.
Funding
Abstract
Aromatase inhibitors (AI) are rapidly becoming the first choice for hormonal treatment of estrogen receptor-alpha (ERalpha)-positive breast cancer in postmenopausal women. However, de novo and acquired resistance frequently occurs. We have previously identified a lysine to arginine transition at residue 303 (K303R) in ERalpha in premalignant breast lesions and invasive breast cancers, which confers estrogen hypersensitivity and resistance to tamoxifen treatment. Thus, we questioned whether resistance to AIs could arise in breast cancer cells expressing the ERalpha mutation. As preclinical models to directly test this possibility, we generated K303R-overexpressing MCF-7 cells stably transfected with an aromatase expression vector. Cells were stimulated with the aromatase substrate, androstenedione, with or without the AI anastrozole (Ana). We found that Ana decreased androstenedione-stimulated growth of wild-type cells, whereas K303R-expressing cells were resistant to the inhibitory effect of Ana on growth. We propose that a mechanism of resistance involves an increased binding between the mutant receptor and the p85alpha regulatory subunit of phosphatidylinositol-3-OH kinase (PI3K), leading to increased PI3K activity and activation of protein kinase B/Akt survival pathways. Inhibition of the selective "addiction" to the PI3K/Akt pathway reversed AI resistance associated with expression of the mutant receptor. Our findings suggest that the K303R ERalpha mutation might be a new predictive marker of response to AIs in mutation-positive breast tumors, and that targeting the PI3K/Akt pathway may be a useful strategy for treating patients with tumors resistant to hormone therapy.
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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.