Significant disparity in the incidence and clinical outcome of prostate cancer (PCa) exist between African- American (AA) men and their European American (EA) counterparts. Despite this recognition, we have not made a major leap in our understanding of the molecular causes associated with such disparity. This proposal is built upon our strong preliminary data on a proto-oncogene, Myb, which has remained largely unexplored in PCa. Our novel findings demonstrate that 1) Myb expression is significantly elevated in AA PCa with greater overall incidence as compared to EA PCa, 2) low intensity expression of Myb is also detected in some of the benign prostate tissues (BPH) from AA patients, while no expression is detected in EA BPH, 3) AA PCa cell lines (MDaPCa-2b and RC-77/T) exhibit high Myb expression and significant resistance to hormone-depletion and docetaxel (DTX) toxicity, 4) AA PCa cells also display high growth, migratory and invasive potential, which is associated with Myb overexpression, and 5) Myb interacts with AR and modulates the expression of androgen-responsive gene, KLK3/PSA, suggesting their cooperative role in gene regulation. Based on these promising findings, we hypothesize that relative greater incidence and overall expression of Myb in AA PCa cells underlies their inherently greater propensity to metastasize and evade therapeutic intervention. To test this hypothesis, we are proposing three specific aims.
In aim 1, we will investigate the role of Myb in PCa aggressiveness and therapy-resistance. Using luciferase-tagged, Myb-overexpressing or -silenced, paired AA and EA PCa cell lines, we will examine the functional association of Myb with PCa growth and metastasis, and their response to castration- and docetaxel- therapies in an orthotopic mouse model.
In Aim 2, we will examine the functional consequences of Myb-AR interaction and identify their downstream consequences. We will specifically examine whether Myb has a role in AR localization and transcriptional activation. Furthermore, we will assess the effect of Myb on transcriptional reprogramming of AR by using state of the art RNA-Seq and ChIP-Seq approaches. We will determine the shared and independent targets of Myb and AR in PCa cells and examine if Myb alters AR target gene specificity.
In Aim 3, we will determine the clinical relevance of Myb in racial disparity associated with PCa. We will perform immunohistochemical (IHC) analysis to assess Myb and AR expression and localization (cytoplasmic vs. nuclear) in PCa, adjacent BPH, and uninvolved normal tissues from both AA and EA cases. We will then examine their correlation (alone and in combination) with race, tumor grade, metastasis incidence, PSA levels, and patient's survival. Together, these studies will provide experimental, mechanistic and clinical evidence for the role of Myb in aggressive behavior and therapeutic- resistance of PCa, and support the association of Myb with observed racial disparity. In the long-term, the resulting information will be useful in reducing the racial disparities in clinical outcomes of PCa by establishing the clinical utility of Myb as a risk predictor and/or therapeutic target for effective disease management.
Main barrier in achieving progress toward racial disparities reduction in prostate cancer is our limited understanding of the underlying molecular basis. The proposed research will examine the functional and clinical significance of Myb overexpression in prostate cancer aggressiveness and therapeutic resistance, the two major reasons for the poor clinical outcome of African American (AA) patients. The outcomes of our study will allow distinction between clinically indolent and aggressive prostate tumors, and pave the way for novel target-based therapies, which will ultimately reduce the enhanced burden of prostate cancer on African American population and improve overall survival of prostate cancer patients.
|Tyagi, Nikhil; Bhardwaj, Arun; Singh, Ajay P et al. (2014) p-21 activated kinase 4 promotes proliferation and survival of pancreatic cancer cells through AKT- and ERK-dependent activation of NF-?B pathway. Oncotarget 5:8778-89|
|Arora, Sumit; Swaminathan, Suresh K; Kirtane, Ameya et al. (2014) Synthesis, characterization, and evaluation of poly (D,L-lactide-co-glycolide)-based nanoformulation of miRNA-150: potential implications for pancreatic cancer therapy. Int J Nanomedicine 9:2933-42|