2. Academic Validation
  3. 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

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

  • Breast Cancer Res. 2021 May 21;23(1):57. doi: 10.1186/s13058-021-01433-8.
Julien Jacquemetton 1 2 3,  Loay Kassem 4,  Coralie Poulard 1 2 3,  Ahmed Dahmani 5,  Ludmilla De Plater 5,  Elodie Montaudon 5,  Laura Sourd 5,  Ludivine Morisset 5,  Rania El Botty 5,  Sophie Chateau-Joubert 6,  Sophie Vacher 7,  Ivan Bièche 7,  Isabelle Treilleux 1 2 3 8,  Olivier Trédan 1 2 3 9,  Elisabetta Marangoni  # 5,  Muriel Le Romancer  # 10 11 12 13
Affiliations

Affiliations

  • 1 Université de Lyon, F-69000, Lyon, France.
  • 2 Inserm U1052, Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France.
  • 3 CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France.
  • 4 Clinical Oncology Department, Faculty of Medicine, Cairo University, Cairo, Egypt.
  • 5 Translational Research Department, Institut Curie, PSL University, 75005, Paris, France.
  • 6 École Nationale Vétérinaire d'Alfort, BioPôle Alfort, 94704, Maisons-Alfort Cedex, France.
  • 7 Genetics Department, Institut Curie, Paris, France.
  • 8 Pathology Department, Centre Léon Bérard, F-69000, Lyon, France.
  • 9 Medical Oncology Department, Centre Léon Bérard, F-69000, Lyon, France.
  • 10 Université de Lyon, F-69000, Lyon, France. muriel.leromancer@lyon.unicancer.fr.
  • 11 Inserm U1052, Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France. muriel.leromancer@lyon.unicancer.fr.
  • 12 CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France. muriel.leromancer@lyon.unicancer.fr.
  • 13 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.
  • # Contributed equally.
PMID: 34020697 DOI: 10.1186/s13058-021-01433-8
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.

Keywords

Biomarker; Breast cancer; Estrogen signaling; PDX; PI3K; Resistance.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-15244
    99.95%, PI3Kα Inhibitor