Phospho-kinase profile of triple negative breast cancer and androgen receptor signaling.
BACKGROUND
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 PDGFRβ 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, PDGFRβ 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.


CONCLUSIONS
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, PDGFRβ or Erk1/2 for future development.
María D
MD
Cuenca-López
Juan C
JC
Montero
Jorge C
JC
Morales
Aleix
A
Prat
Atanasio
A
Pandiella
Translational Cancer Research Unit, Albacete University Hospital, 02006 Albacete, Spain. albertoo@sescam.jccm.es.
Alberto
A
Ocana
D000813:Anilides / Q000008:administration & dosage; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics*; D058990:Molecular Targeted Therapy; D009570:Nitriles / Q000008:administration & dosage; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000235:genetics; D014105:Tosyl Compounds / Q000008:administration & dosage; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology
C410798:AR protein, human; D000813:Anilides; D009570:Nitriles; D011944:Receptors, Androgen; D014105:Tosyl Compounds; C053541:bicalutamide; C546842:MTOR protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D058570:TOR Serine-Threonine Kinases