ArticleBreast cancer research : BCR2021
Analysis of genomic and non-genomic signaling of estrogen receptor in PDX models of breast cancer treated with a combination of the PI3K inhibitor alpelisib (BYL719) and fulvestrant.
Article in Breast cancer research : BCR, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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12 citing papers in PubMed, 14 citations in OpenAlex.
- Sex differences in non-reproductive cancers: mechanistic roles of sex-hormone signaling.Cell communication and signaling : CCS · 2026Review
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- Improvement of Menopausal Symptoms byFood science & nutrition · 2025Article
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- Role of PRMT1 and PRMT5 in Breast Cancer.International journal of molecular sciences · 2024Review
- Androgen receptor and estrogen receptor variants in prostate and breast cancers.The Journal of steroid biochemistry and molecular biology · 2024Review
- The combination of breast cancer PDO and mini-PDX platform for drug screening and individualized treatment.Journal of cellular and molecular medicine · 2024Article
- Update on Adipose Tissue and Cancer.Endocrine reviews · 2023Article
- Estetrol: From Preclinical to Clinical Pharmacology and Advances in the Understanding of the Molecular Mechanism of Action.Drugs in R&D · 2023Review
- Decoding the Therapeutic Implications of the ERα Stability and Subcellular Distribution in Breast Cancer.Frontiers in endocrinology · 2022Review
- Targeting AKT in ER-Positive HER2-Negative Metastatic Breast Cancer: From Molecular Promises to Real Life Pitfalls?International journal of molecular sciences · 2021Review
- Structure, Activity, and Function of PRMT1.Life (Basel, Switzerland) · 2021Review
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16 authors at 8 institutions in 2 countries.
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Abstract
backgroundEndocrine therapies targeting estrogen signaling have significantly improved breast cancer (BC) patient survival, although 40% of ERα-positive BCs do not respond to those therapies. Aside from genomic signaling, estrogen triggers non-genomic pathways by forming a complex containing methylERα/Src/PI3K, a hallmark of aggressiveness and resistance to tamoxifen. We aimed to confirm the prognostic value of this complex and investigated whether its targeting could improve tumor response in vivo.
methodsThe interaction of ERα/Src and ERα/PI3K was studied by proximity ligation assay (PLA) in a cohort of 440 BC patients. We then treated patient-derived BC xenografts (PDXs) with fulvestrant or the PI3K inhibitor alpelisib (BYL719) alone or in combination. We analyzed their anti-proliferative effects on 6 ERα+ and 3 ERα- PDX models. Genomic and non-genomic estrogen signaling were assessed by measuring ERα/PI3K interaction by PLA and the expression of estrogen target genes by RT-QPCR, respectively.
resultsWe confirmed that ERα/Src and ERα/PI3K interactions were associated with a trend to poorer survival, the latter displaying the most significant effects. In ERα+ tumors, the combination of BYL719 and fulvestrant was more effective than fulvestrant alone in 3 models, irrespective of PI3K, PTEN status, or ERα/PI3K targeting. Remarkably, resistance to fulvestrant was associated with non-genomic ERα signaling, since genomic degradation of ERα was unaltered in these tumors, whereas the treatment did not diminish the level of ERα/PI3K interaction. Interestingly, in 2 ERα- models, fulvestrant alone impacted tumor growth, and this was associated with a decrease in ERα/PI3K interaction.
conclusionsOur results demonstrate that ERα/PI3K may constitute a new prognostic marker, as well as a new target in BC. Indeed, resistance to fulvestrant in ERα+ tumors was associated with a lack of impairment of ERα/PI3K interaction in the cytoplasm. In addition, an efficient targeting of ERα/PI3K in ERα- tumors could constitute a promising therapeutic option.
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