PMID- 19016759
OWN - NLM
STAT- MEDLINE
DCOM- 20081217
LR  - 20131121
IS  - 1349-7006 (Electronic)
IS  - 1347-9032 (Linking)
VI  - 99
IP  - 10
DP  - 2008 Oct
TI  - mTOR inhibition reverses acquired endocrine therapy resistance of breast cancer 
      cells at the cell proliferation and gene-expression levels.
PG  - 1992-2003
LID - 10.1111/j.1349-7006.2008.00955.x [doi]
AB  - 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 
      (ERalpha)-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 ERalpha-positive human breast adenocarcinoma 
      derived-MCF-7 cells used in this study have acquired both cross-resistance to 
      hydroxy-tamoxifen (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 ERalpha protein expression levels and modification of 
      the balance of phospho-ser167 ERalpha/total ERalpha 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 ERalpha-positive endocrine therapy-resistant breast cancers.
FAU - Ghayad, Sandra E
AU  - Ghayad SE
AD  - Universite de Lyon, Lyon, France.
FAU - Bieche, Ivan
AU  - Bieche I
FAU - Vendrell, Julie A
AU  - Vendrell JA
FAU - Keime, Celine
AU  - Keime C
FAU - Lidereau, Rosette
AU  - Lidereau R
FAU - Dumontet, Charles
AU  - Dumontet C
FAU - Cohen, Pascale A
AU  - Cohen PA
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Cancer Sci
JT  - Cancer science
JID - 101168776
RN  - 0 (Receptors, Estrogen)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Breast Neoplasms/*drug therapy/genetics/pathology
MH  - Cell Line, Tumor
MH  - Cell Proliferation/*drug effects
MH  - Drug Resistance, Neoplasm/*drug effects
MH  - Female
MH  - Gene Expression Regulation, Neoplastic/*drug effects
MH  - Humans
MH  - Models, Genetic
MH  - Receptors, Estrogen/genetics
MH  - Sirolimus/*pharmacology
EDAT- 2008/11/20 09:00
MHDA- 2008/12/18 09:00
CRDT- 2008/11/20 09:00
PHST- 2008/11/20 09:00 [pubmed]
PHST- 2008/12/18 09:00 [medline]
PHST- 2008/11/20 09:00 [entrez]
AID - CAS955 [pii]
AID - 10.1111/j.1349-7006.2008.00955.x [doi]
PST - ppublish
SO  - Cancer Sci. 2008 Oct;99(10):1992-2003. doi: 10.1111/j.1349-7006.2008.00955.x.