Abstract
BackgroundThe 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.MethodsWe 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.ResultsAR 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.ConclusionOur 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.
Highlights
The androgen receptor (AR) plays a central role in the oncogenesis of different tumors, as is the case in prostate cancer
We evaluated the expression of the AR in 16 human samples from triple negative breast cancer patients
Expression of the androgen receptor correlates by activated receptor tyrosine kinases in human samples Given the fact that one of the mechanisms that control the expression of the AR in prostate cancer is linked with kinase signaling pathways, we evaluated if the activation of membrane RTKs or their downstream pathways could be associated with the expression of the AR
Summary
The androgen receptor (AR) plays a central role in the oncogenesis of different tumors, as is the case in prostate cancer. In addition the androgen receptor (AR) is expressed in breast cancer in 60%–70% of tumors regardless of the ER status [6] and has been linked with a good outcome in ER positive tumors [7] This good prognosis is associated with the impeding of the transcriptional activity mediated by the ER [7]. In the apocrine breast cancer subtype- an ER negative tumorthe AR acts by binding to the same transcription factors as the ER does, mainly through FOXA1, leading to a luminal gene expression phenotype [8] In this case the expression of AR is associated with worse prognosis [8]. Using gene expression analyses TNBC has been classified in subtypes including one termed luminal androgen that was enriched in genes related to this pathway [9]
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