Elisabetta Marangoni1, Muriel Le Romancer2,3,4,5, Julien Jacquemetton6,7,8, Loay Kassem9, Coralie Poulard6,7,8, Ahmed Dahmani1, Ludmilla De Plater1, Elodie Montaudon1, Laura Sourd1, Ludivine Morisset1, Rania El Botty1, Sophie Chateau-Joubert10, Sophie Vacher11, Ivan Bièche11, Isabelle Treilleux6,7,8,12, Olivier Trédan6,7,8,13. 1. Translational Research Department, Institut Curie, PSL University, 75005, Paris, France. 2. Université de Lyon, F-69000, Lyon, France. muriel.leromancer@lyon.unicancer.fr. 3. Inserm U1052, Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France. muriel.leromancer@lyon.unicancer.fr. 4. CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France. muriel.leromancer@lyon.unicancer.fr. 5. Centre de Recherche en Cancérologie de Lyon, INSERM 1052, CNRS 5286, Centre Léon Bérard, Bâtiment D, 28 rue Laennec, 69373, Lyon Cedex 08, France. muriel.leromancer@lyon.unicancer.fr. 6. Université de Lyon, F-69000, Lyon, France. 7. Inserm U1052, Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France. 8. CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France. 9. Clinical Oncology Department, Faculty of Medicine, Cairo University, Cairo, Egypt. 10. École Nationale Vétérinaire d'Alfort, BioPôle Alfort, 94704, Maisons-Alfort Cedex, France. 11. Genetics Department, Institut Curie, Paris, France. 12. Pathology Department, Centre Léon Bérard, F-69000, Lyon, France. 13. Medical Oncology Department, Centre Léon Bérard, F-69000, Lyon, France.
Abstract
BACKGROUND: Endocrine 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. METHODS: The 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. RESULTS: We 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. CONCLUSIONS: Our 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.
BACKGROUND: Endocrine 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. METHODS: The 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. RESULTS: We 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. CONCLUSIONS: Our 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.
Entities:
Keywords:
Biomarker; Breast cancer; Estrogen signaling; PDX; PI3K; Resistance
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