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
; 23(1): 57, 2021 05 21.
Article
en En
| MEDLINE
| ID: mdl-34020697
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.Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Tiazoles
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Neoplasias de la Mama
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Protocolos de Quimioterapia Combinada Antineoplásica
/
Receptores de Estrógenos
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Fulvestrant
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Inhibidores de las Quinasa Fosfoinosítidos-3
Tipo de estudio:
Prognostic_studies
Límite:
Animals
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Female
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Humans
/
Middle aged
Idioma:
En
Revista:
Breast Cancer Res
Asunto de la revista:
NEOPLASIAS
Año:
2021
Tipo del documento:
Article
País de afiliación:
Francia