Phospho-kinase profile of triple negative breast cancer and androgen receptor signaling


The androgen receptor (AR) plays a central role in the oncogenesis of different tumors, as is the case in prostate cancer. In triple negative breast cancer (TNBC) a gene expression classification has described different subgroups including a luminal androgen subtype.

The AR can be controlled by several mechanisms like the activation of membrane tyrosine kinases and downstream signaling pathways. However little is known in TNBC about how the AR is modulated by these mechanisms and the potential therapeutic strategists to inhibit its expression.

Methods: We used human samples to evaluate the expression of AR by western-blot and phospho-proteomic kinase arrays that recognize membrane tyrosine kinase receptors and downstream mediators.

Western-blots in human cell lines were carried out to analyze the expression and activation of individual proteins. Drugs against these kinases in different conditions were used to measure the expression of the androgen receptor.

PCR experiments were performed to assess changes in the AR gene after therapeutic modulation of these pathways.

Results: AR is present in a subset of TNBC and its expression correlates with activated membrane receptor kinases-EGFR and PDGFRbeta in human samples and cell lines. Inhibition of the PI3K/mTOR pathway in TNBC cell lines decreased notably the expression of the AR.

Concomitant administration of the anti-androgen bicalutamide with the EGFR, PDGFRbeta and Erk1/2 inhibitors, decreased the amount of AR compared to each agent given alone, and had an additive anti-proliferative effect. Administration of dihydrotestosterone augmented the expression of AR that was not modified by the inhibition of the PI3K/mTOR or Erk1/2 pathways.

AR expression was posttranscriptionally regulated by PI3K or Erk1/2 inhibition.

Conclusion: Our results describe the expression of the AR in TNBC as a druggable target and further suggest the combination of bicalutamide with inhibitors of EGFR, PDGFRbeta or Erk1/2 for future development.

Author: María D Cuenca-LópezJuan C MonteroJorge C MoralesAleix PratAtanasio PandiellaAlberto Ocana
Credits/Source: BMC Cancer 2014, 14:302



Published on: 2014-04-30



News Provider: 7thSpace Interactive / EUPB Press Office

Copyright by the authors listed above - made available via BioMedCentral (Open Access). Please make sure to read our disclaimer prior to contacting 7thSpace Interactive. To contact our editors, visit our online helpdesk. If you wish submit your own press release, click here.

Social Bookmarking
RETWEET This! | Digg this! | Post to del.icio.us | Post to Furl | Add to Netscape | Add to Yahoo! | Rojo



Comments

There are no comments available. Be the first to write a comment.


You need to enable Javascript to post a comment.


Custom Search

Username
Password










© 2014 7thSpace Interactive
All Rights Reserved - About | Disclaimer | Helpdesk