Abstract
Prostate cancer (PCa) is the most commonly diagnosed neoplasm and the second leading cause of cancer-related deaths in men. Acquisition of resistance to conventional therapy is a major problem for PCa patient management. Several mechanisms have been described to promote therapy resistance in PCa, such as androgen receptor (AR) activation, epithelial-to-mesenchymal transition (EMT), acquisition of stem cell properties and neuroendocrine transdifferentiation (NEtD). Recently, we identified Brachyury as a new biomarker of PCa aggressiveness and poor prognosis. In the present study we aimed to assess the role of Brachyury in PCa therapy resistance. We showed that Brachyury overexpression in prostate cancer cells lines increased resistance to docetaxel and cabazitaxel drugs, whereas Brachyury abrogation induced decrease in therapy resistance. Through ChiP-qPCR assays we further demonstrated that Brachyury is a direct regulator of AR expression as well as of the biomarker AMACR and the mesenchymal markers Snail and Fibronectin. Furthermore, in vitro Brachyury was also able to increase EMT and stem properties. By in silico analysis, clinically human Brachyury-positive PCa samples were associated with biomarkers of PCa aggressiveness and therapy resistance, including PTEN loss, and expression of NEtD markers, ERG and Bcl-2. Taken together, our results indicate that Brachyury contributes to tumor chemotherapy resistance, constituting an attractive target for advanced PCa patients.
Highlights
Prostate cancer (PCa) is the most prevalent malignancy in men and the second leading cause of cancerrelated deaths [1]
These results indicate that Brachyury alone or in combination with AMACR, could be used in routine setting as a PCa diagnosis biomarker
We believe that correlation of Brachyury and androgen receptor (AR) in the nucleus could be a direct consequence of Brachyury role in activation AR expression and therapy resistance
Summary
Prostate cancer (PCa) is the most prevalent malignancy in men and the second leading cause of cancerrelated deaths [1]. The fist-line therapy for PCa patients includes the blockade of androgen receptor (AR) activation and signaling based on androgen-deprivation therapy This approach is effective at an early phase, but eventually tumors recur, leading to the known metastatic castrationresistant prostate cancer (mCRPC) with a lethal outcome [3]. It was proposed that it arises when cancer cells either maintain AR signaling in the absence of normal levels of ligand or no longer require activation of this pathway for survival and proliferation [11] It has been suggested an association between www.impactjournals.com/oncotarget chemoresistance and epithelial-to-mesenchymal transition (EMT) in PCa, a mechanism by which cancer cells acquire a higher capacity to invade and further metastasize [13], as well as increased stem cell features (e.g. CD15 and CD133) [14, 15]. In the mCRPC patients with docetaxel-resistant phenotypes, it has been shown the survival benefit with second-line therapy using new drugs such as enzalutamide, abiraterone and cabazitaxel [7,8,9,10]
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