Analysis of A Novel Nonsense Mutation of Androgen Receptor Gene in Castration-Resistant Prostate Cancer

BACKGROUND: Prostate cancer (PCa) is the second leading cause of cancer mortality in American men. The standard treatment for PCa is androgen deprivation therapy (ADT) that blocks transcriptional activity of androgen receptor, but ADT invariably leads to the development of castration-resistant form of PCa (CRPC) with restored activity of AR. CRPC can be further treated with more intensive ADTs, including CYP17-inhibitors to block intratumoral androgen synthesis and more potent AR antagonist (enzalutamide). Most CRPC patients still relapse after a year of treatment and AR activity appears to be restored again. By analyzing the tumor mRNA from a CRPC patient biopsy who had developed resistance to CYP17-inhibitor treatment, we identified a novel nonsense AR mutation on ligand binding domain (Q784sc), which presumably produces a C-terminal truncated form of AR protein that lacks ligand binding domain (LBD) and may mimic certain AR splice variants that also lack LBD. We thus hypothesized that AR-Q784sc mutant may gain the androgen-independent activity or may enhance the transcriptional activity of full-length AR under low androgen environment through dimerization with full-length AR. METHOD: We utilized luciferase reporter assays to assess the activity of AR-Q784sc in absence or presence of androgens, and with/out full-length AR. We also examined the protein stability and cellular localization of AR-Q784sc using immunoblotting and immunofluorescence. Moreover, stable cell lines that overexpress AR and/or AR-Q784sc were generated to assess the transcription activity on endogenous target genes and on PCa cell growth. CONCLUSION: AR-Q784sc mutant produces a LBD truncated AR protein that does not have any transcriptional activity by it alone. However, AR-Q784sc can significantly enhance transcriptional activity of full-length AR though dimerization, indicating that the more intensive ADTs may allow CRPC cells to select for LBD truncated form of AR to further enhance the full-length AR activity under low androgen environment

ErbB2 Signaling Increases Androgen Receptor Expression in Abiraterone-Resistant Prostate Cancer

Purpose: ErbB2 signaling appears to be increased and may enhance AR activity in a subset of CRPC, but agents targeting ErbB2 have not been effective. This study was undertaken to assess ErbB2 activity in abiraterone-resistant prostate cancer (PCa), and determine whether it may contribute to androgen receptor (AR) signaling in these tumors. Experimental Design: AR activity and ErbB2 signaling were examined in the radical prostatectomy specimens from a neoadjuvant clinical trial of leuprolide plus abiraterone, and in the specimens from abiraterone-resistant CRPC xenograft models. The effect of ErbB2 signaling on AR activity was determined in two CRPC cell lines. Moreover, the effect of combination treatment with abiraterone and an ErbB2 inhibitor was assessed in a CRPC xenograft model. Results: We found that ErbB2 signaling was elevated in residual tumor following abiraterone treatment in a subset of patients, and was associated with higher nuclear AR expression. In xenograft models, we similarly demonstrated that ErbB2 signaling was increased and associated with AR reactivation in abiraterone-resistant tumors, while ERBB2 message level was not changed. Mechanistically, we show that ErbB2 signaling and subsequent activation of the PI3K/AKT signaling stabilizes AR protein. Inhibitors targeting ErbB2/PI3K/AKT pathway disrupt AR transcriptional activity. Furthermore, concomitantly treating CRPC xenograft with abiraterone and an ErbB2 inhibitor, lapatinib, blocked AR reactivation and suppressed tumor progression. Conclusions: ErbB2 signaling is elevated in a subset of abiraterone-resistant prostate cancer patients and stabilizes AR protein. Combination therapy with abiraterone and ErbB2 antagonists may be effective for treating the subset of CRPC with elevated ErbB2 activity

Protein phosphatase 1 suppresses androgen receptor ubiquitylation and degradation

The phosphoprotein phosphatases are emerging as important androgen receptor (AR) regulators in prostate cancer (PCa). We reported previously that the protein phosphatase 1 catalytic subunit (PP1α) can enhance AR activity by dephosphorylating a site in the AR hinge region (Ser650) and thereby decrease AR nuclear export. In this study we show that PP1α increases the expression of wildtype as well as an S650A mutant AR, indicating that it is acting through one or more additional mechanisms. We next show that PP1α binds primarily to the AR ligand binding domain and decreases its ubiquitylation and degradation. Moreover, we find that the PP1α inhibitor tautomycin increases phosphorylation of AR ubiquitin ligases including SKP2 and MDM2 at sites that enhance their activity, providing a mechanism by which PP1α may suppress AR degradation. Significantly, the tautomycin mediated decrease in AR expression was most pronounced at low androgen levels or in the presence of the AR antagonist enzalutamide. Consistent with this finding, the sensitivity of LNCaP and C4–2 PCa cells to tautomycin, as assessed by PSA synthesis and proliferation, was enhanced at low androgen levels or by treatment with enzalutamide. Together these results indicate that PP1α may contribute to stabilizing AR protein after androgen deprivation therapies, and that targeting PP1α or the AR-PP1α interaction may be effective in castration-resistant prostate cancer (CRPC)

Knowledge-Enhanced Scene Graph Generation with Multimodal Relation Alignment (Student Abstract)

Existing scene graph generation methods suffer the limitations when the image lacks of sufficient visual contexts. To address this limitation, we propose a knowledge-enhanced scene graph generation model with multimodal relation alignment, which supplements the missing visual contexts by well-aligned textual knowledge. First, we represent the textual information into contextualized knowledge which is guided by the visual objects to enhance the contexts. Furthermore, we align the multimodal relation triplets by co-attention module for better semantics fusion. The experimental results show the effectiveness of our method

Learning Modality-Invariant Features by Cross-Modality Adversarial Network for Visual Question Answering

Visual Question Answering (VQA) is a typical multimodal task with significant development prospect on web application. In order to answer the question based on the corresponding image, a VQA model needs to utilize the information from different modality efficiently. Although the multimodal fusion methods such as attention mechanism make significant contribution for VQA, these methods try to co-learn the multimodal features directly, ignoring the large gap between different modality and thus poor aligning the semantic. In this paper, we propose a Cross-Modality Adversarial Network (CMAN) to address this limitation. Our method combines cross-modality adversarial learning with modality-invariant attention learning aiming to learn the modality-invariant features for better semantic alignment and higher answer prediction accuracy. The accuracy of model achieves 70.81% on the test-dev split on the VQA-v2 dataset. Our results also show that the model narrows the gap between different modalities effectively and improves the alignment performance of the multimodal information.</p

Pioneer of prostate cancer: past, present and the future of FOXA1

Abstract Prostate cancer is the most commonly diagnosed non-cutaneous cancers in North American men. While androgen deprivation has remained as the cornerstone of prostate cancer treatment, resistance ensues leading to lethal disease. Forkhead box A1 (FOXA1) encodes a pioneer factor that induces open chromatin conformation to allow the binding of other transcription factors. Through direct interactions with the Androgen Receptor (AR), FOXA1 helps to shape AR signaling that drives the growth and survival of normal prostate and prostate cancer cells. FOXA1 also possesses an AR-independent role of regulating epithelial-to-mesenchymal transition (EMT). In prostate cancer, mutations converge onto the coding sequence and cis-regulatory elements (CREs) of FOXA1, leading to functional alterations. In addition, FOXA1 activity in prostate cancer can be modulated post-translationally through various mechanisms such as LSD1-mediated protein demethylation. In this review, we describe the latest discoveries related to the function and regulation of FOXA1 in prostate cancer, pointing to their relevance to guide future clinical interventions