Despite androgen receptor (AR) targeting having become the most important therapeutic strategy for treating prostate cancer, most tumors progress to castration-resistant prostate cancer (CRPC) under androgen deprivation therapy (ADT), after which conventional treatment is ineffective. In this proposed study, we will specifically investigate how components of the AR axis mediate prostate cancer progression and confer therapy resistance to cancer cells. We propose that an extracellular matrix (ECM) component-secreted protein, transforming growth factor-β-induced (TGFBI/BIGH3), was associated with prostate cancer epithelialmesenchymal transition (EMT) and activation in androgen-deprived prostate cancer cells with a variety of metastatic properties. SPDEF was found to be regulated by the AR, and loss of SPDEF was associated with increased prostate cancer aggressiveness. We found that there is a novel positive association between the induction of TGFBI and inactivation of AR-SPDEF signaling. We will further identify whether the regulatory mechanisms by which AR-regulated SPDEF repressed TGFBI expression. The role of TGFBI in metastatic CRPC is largely unknown. We found that treatment of the CRPC cells with an AR antagonist, MDV3100, resulted in stimulated EMT and increased TGFBI mRNA and protein expression. Our bioinformatic analyses revealed that tumors with higher TGFBI levels are associated with activated EMT signaling, as denoted by an EMT-responsive gene signature set. We identified MMP2 and CCL2 as two robust stimulating genes whose expression was associated with the EMT signaling gene signature in tissues with higher levels of TGFBI. Following interrogation of a clinical prostate cancer database, we found that an increased level of MMP2 and CCL2 was negatively associated with TGFBI expression. TGFBI was shown to regulate the metastatic process of lymphatic endothelial cells under hypoxic conditions. We will now test whether MMP2 and CCL2 levels are correlated with TGFBI levels in hypoxic conditions of prostate cancer. We hypothesize that the effect of hypoxia may induce TGFBI expression and in turn contribute to prostate malignancy by modulating MMP2 and CCL2 expression. We will explore whether androgen deprivation treatment induces TGFBI expression and promotes bone metastases by upregulating MMP2 and CCL2 in a prostate cancer xenograft model. We anticipate that the induction of TGFBI results in increased prostate cancer bone metastasis that is linked to dysregulation of the AR signaling pathway through hypoxia. Therefore, the regulatory mechanisms inactivating TGFBI in addition to targeting AR signaling in metastatic CRPC will be further investigated: The investigations in this three-year project are as follows: Specific Aim I: Investigate the transcriptional regulatory network of the SPDEFmediated TGFBI gene in response to ADT resistance leading to prostate cancer progression and metastasis using both in vitro and in vivo models. Specific Aim II: Identify novel metalloproteinases and cytokines that interact with TGFBI and determine the molecular basis of the relationship among oxidative stress, SPDEF, and EMT in metastatic CRPC. Specific Aim III: Determine the biological functions of TGFBI that regulate resistance to AR antagonists in metastatic CRPC and explore the therapeutic response of the blockage of TGFBI by re-sensitizing the CRPC cells to ADT.
|Effective start/end date||8/1/17 → 7/31/18|
- castration resistant prostate cancer (CRPC)
- androgen deprivation therapy (ADT)
- epithelial-mesenchymal transition (EMT)
- androgen receptor (AR)
- transforming growth factor-β- induced (TGFBI)