Overcoming acquired resistance to letrozole by targeting the PI3K/AKT/mTOR pathway in breast cancer cell clones

被引：98

作者：

Cavazzoni, Andrea ^{[1
]}

Bonelli, Mara A. ^{[1
]}

Fumarola, Claudia ^{[1
]}

La Monica, Silvia ^{[1
]}

Airoud, Kinda ^{[1
]}

Bertoni, Ramona ^{[1
]}

Alfieri, Roberta R. ^{[1
]}

Galetti, Maricla ^{[1
,2
]}

Tramonti, Stefano ^{[1
]}

Galvani, Elena ^{[1
]}

Harris, Adrian L. ^{[3
]}

Martin, Lesley-Ann ^{[4
]}

Andreis, Daniele ^{[5
]}

Bottini, Alberto ^{[5
]}

Generali, Daniele ^{[5
,6
]}

Petronini, Pier Giorgio ^{[1
]}

机构：

[1] Univ Parma, Dept Expt Med, Unit Expt Oncol, I-43100 Parma, Italy

[2] Univ Parma, Italian Workers Compensat Author INAIL Res Ctr, I-43100 Parma, Italy

[3] Univ Oxford, John Radcliffe Hosp, Weatherall Inst Mol Med, Mol Oncol Labs, Oxford OX3 9DU, England

[4] Inst Canc Res, Breakthrough Breast Canc Ctr, London SW3 6JB, England

[5] Ist Ospitalieri Cremona, Breast Canc Unit, Cremona, Italy

[6] Ist Ospitalieri Cremona, Ctr Med Mol, Cremona, Italy

来源：

CANCER LETTERS | 2012年 / 323卷 / 01期

关键词：

Breast; Letrozole; Resistance; AKT; mTOR; TERM ESTROGEN DEPRIVATION; DUAL PI3K/MTOR INHIBITOR; ENDOCRINE THERAPY; AROMATASE INHIBITOR; TUBEROUS SCLEROSIS; RAD001; EVEROLIMUS; RANDOMIZED-TRIAL; IN-VITRO; GROWTH; TAMOXIFEN;

D O I：

10.1016/j.canlet.2012.03.034

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

Development of resistance to endocrine therapy is a clinical issue in estrogen receptor (ER)-positive breast cancer. Here we show that persistent activation of AKT/mTOR signaling is crucial to the acquisition of letrozole resistance in cell clones generated from MCF-7/AROM-1 aromatase-expressing breast cancer cells after prolonged letrozole exposure. ER alpha plays a marginal role in this context. As a proof of concept, the association between PI3K/AKT/mTOR signaling and insensitivity to endocrine therapies was confirmed in breast cancer patients who developed early letrozole resistance in neoadjuvant setting. In addition our results suggest that, regardless of the mechanism mediating the activation of AKT/mTOR pathway, either RAD001 or NVP-8EZ235 treatment may represent a promising strategy to overcome acquired resistance to letrozole in breast cancers dependent on AKT/mTOR signaling. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

引用

页码：77 / 87

页数：11

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