mTOR inhibition reverses acquired endocrine therapy resistance of breast cancer cells at the cell proliferation and gene‐expression levels
Résumé
Activation of the Akt/mammalian target of rapamycin (mTOR) pathway has been shown to be associated with resistance to endocrine therapy in estrogen receptor alpha (ERa)-positive breast cancer patients. Utmost importance is attached to strategies aimed at overcoming treatment resistance. In this context, this work aimed to investigate whether, in breast cancer cells, the use of an mTOR inhibitor would be sufficient to reverse the resistance acquired after exposure to endocrine therapy. The ERa-positive human breast adenocarcinoma derived-MCF-7 cells used in this study have acquired both cross-resistance to hydroxytamoxifen (OH-Tam) and to fulvestrant and strong activation of the Akt/mTOR pathway. Cell proliferation tests in control cells demonstrated that the mTOR inhibitor rapamycin enhanced cell sensitivity to endocrine therapy when combined to OH-Tam or to fulvestrant. In resistant cells, rapamycin used alone greatly inhibited cell proliferation and reversed resistance to endocrine therapy by blocking the agonist-like activity of OH-Tam on cell proliferation and bypassing fulvestrant resistance. Reversion of resistance by rapamycin was associated with increased ERa protein expression levels and modification of the balance of phospho-ser167 ERa/total ERa ratio. Pangenomic DNA array experiments demonstrated that the cotreatment of resistant cells with fulvestrant and rapamycin allowed the restoration of 40% of the fulvestrant gene-expression signature. Taken together, data presented herein strongly support the idea that mTOR inhibitor might be one of the promising therapeutic approaches for patients with ERa-positive endocrine therapy-resistant breast cancers.
Mots clés
mTOR
mammalian target of rapamycin ERα
estrogen receptor alpha OH-Tam
hydroxy-tamoxifen ER+
ERα-positive SERD
selective estrogen receptor down-regulator SERM
selective estrogen receptor modulator Tam
tamoxifen PI3K
phosphatidylinositol 3-kinase Akt/PKB
protein kinase B E 2
17β-estradiol BrdU
5bromodeoxyuridine GCOS
GeneChip Operating Software RMA
Robust Multi-array Average GO
Gene Ontology RTQ-PCR
Real-Time Quantitative PCR
mammalian target of rapamycin
ERα
estrogen receptor alpha
OH-Tam
hydroxy-tamoxifen
ER+
ERα-positive
SERD
selective estrogen receptor down-regulator
SERM
selective estrogen receptor modulator
Tam
tamoxifen
PI3K
phosphatidylinositol 3-kinase
Akt/PKB
protein kinase B
E 2
17β-estradiol
BrdU
5bromodeoxyuridine
GCOS
GeneChip Operating Software
RMA
Robust Multi-array Average
GO
Gene Ontology
RTQ-PCR
Domaines
Sciences du Vivant [q-bio]
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Licence : Copyright (Tous droits réservés)
Licence : Copyright (Tous droits réservés)