Skip Navigation

Annals of Oncology 2007 18(8):1323-1328; doi:10.1093/annonc/mdm170
This Article
Right arrow Full Text Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (16)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Beeram, M
Right arrow Articles by deGraffenried, L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Beeram, M
Right arrow Articles by deGraffenried, L.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© 2007 European Society for Medical Oncology

breast cancer

Akt-induced endocrine therapy resistance is reversed by inhibition of mTOR signaling

M Beeram1, Q-TN Tan2, RR Tekmal3, D Russell1, A Middleton1 and LA deGraffenried1,*

1 Department of Medical Oncology
2 Department of Orthodontics
3 Department of Obstetrics and Gynecology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA

* Correspondence to: Prof. L. A. deGraffenried, Division of Medical Oncology, MSC 7884, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA. Tel: +1-210-567-4739; Fax: +1-210-567-6687; E-mail: degraffenri{at}uthscsa.edu

Background: Resistance to endocrine therapy is a major impediment in breast cancer therapeutics. The Phosphatidylinositol-3-OH kinase (PI3K)/Protein kinase B (Akt/PKB) kinase signaling pathway has been implicated in altering breast cancer response to multiple therapies. How Akt modulates response is an area of significant clinical relevance.

Methods: We have used an in vitro model to discern the effects of robust Akt activity on breast cancer cellular response to endocrine therapies.

Results: High levels of Akt activity confer resistance to the aromatase inhibitor Letrozole (Let) and the selective estrogen receptor (ER) down-regulator Fulvestrant (ICI). Akt-induced resistance is not due to failure of these endocrine agents to inhibit estrogen receptor {alpha} activity. Instead, resistance is characterized by altered cell cycle and apoptotic response. Cotreatment with low concentrations of the mTOR inhibitor RAD-001 and either Let or ICI restores response of the resistant cells to levels observed in the responsive cells treated with either Let or ICI as a single agent.

Conclusions: Our preliminary findings in experiments with RAD-001 indicate that cotreatment with mTOR inhibitors and either Let or ICI reverses the Akt-mediated resistance and restores responsiveness to antiestrogens. Concurrent ER and mTOR inhibition is therefore an effective strategy to overcome growth factor-induced resistance and bears significant implications for optimal clinical development of these agents in breast cancer treatment.

Key words: Akt, breast cancer, endocrine therapy, mTOR

Received for publication August 23, 2006. Revision received February 26, 2007. Accepted for publication March 30, 2007.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 JCOHome page
S. L. Ellard, M. Clemons, K. A. Gelmon, B. Norris, H. Kennecke, S. Chia, K. Pritchard, A. Eisen, T. Vandenberg, M. Taylor, et al.
Randomized Phase II Study Comparing Two Schedules of Everolimus in Patients With Recurrent/Metastatic Breast Cancer: NCIC Clinical Trials Group IND.163
J. Clin. Oncol., September 20, 2009; 27(27): 4536 - 4541.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
J. Baselga, V. Semiglazov, P. van Dam, A. Manikhas, M. Bellet, J. Mayordomo, M. Campone, E. Kubista, R. Greil, G. Bianchi, et al.
Phase II Randomized Study of Neoadjuvant Everolimus Plus Letrozole Compared With Placebo Plus Letrozole in Patients With Estrogen Receptor-Positive Breast Cancer
J. Clin. Oncol., June 1, 2009; 27(16): 2630 - 2637.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
D. Tripathy
Are We Hitting the Right Combination for Hormonally Sensitive Breast Cancer?
J. Clin. Oncol., June 1, 2009; 27(16): 2580 - 2582.
[Full Text] [PDF]

Home page
 JCOHome page
F. Meric-Bernstam and A. M. Gonzalez-Angulo
Targeting the mTOR Signaling Network for Cancer Therapy
J. Clin. Oncol., May 1, 2009; 27(13): 2278 - 2287.
[Abstract] [Full Text] [PDF]

Home page
 Ann OncolHome page
S Dawood and M Cristofanilli
Endocrine resistance in breast cancer: what really matters?
Ann. Onc., August 1, 2007; 18(8): 1289 - 1291.
[Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.