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- Title
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.
- Authors
Jacquemetton, Julien; Kassem, Loay; Poulard, Coralie; Dahmani, Ahmed; De Plater, Ludmilla; Montaudon, Elodie; Sourd, Laura; Morisset, Ludivine; El Botty, Rania; Chateau-Joubert, Sophie; Vacher, Sophie; Bièche, Ivan; Treilleux, Isabelle; Trédan, Olivier; Marangoni, Elisabetta; Le Romancer, Muriel
- Abstract
<bold>Background: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusions: </bold>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.
- Subjects
BREAST cancer; ESTROGEN receptors; ESTROGEN; GENOMICS; PHOSPHATIDYLINOSITOL 3-kinases; PROGNOSIS
- Publication
Breast Cancer Research, 2021, Vol 23, Issue 1, p57
- ISSN
1465-5411
- Publication type
journal article
- DOI
10.1186/s13058-021-01433-8