Androgen Receptor In Tumor Cells Research Articles

Abstract A048: Bone remodeling in relation to androgen receptor activity in prostate cancer bone metastases

Abstract Prostate cancer often metastasizes to bone and the metastases are generally classified as osteoblastic, although a mixed osteoblastic/osteolytic bone response may exist. The present study aimed to characterize the bone remodeling activity in clinical bone metastasis samples, with the overall hypothesis that diversities exist that may be of importance for clinical response to current therapies. Specifically, we aimed to study bone remodeling activity in relation to tumor cell androgen receptor (AR) activity. Metastasis tissue obtained from treatment-naïve (n=11) and castration-resistant (n=28) patients during surgery for spinal cord compression was characterized using whole-genome expression analysis followed by multivariate modeling and functional enrichment analysis as well as by histologic evaluation. By analyzing expression levels of a predefined set of markers representing osteoclasts (ACP5, CTSK, MMP9), osteoblasts (ALPL, BGLAP, RUNX2), and osteocytes (SOST), we found high osteoblast activity to be coupled to high osteoclast activity. Immunohistochemistry verified a significant correlation between RUNX2-positive osteoblasts and TRAP (ACP5)-positive osteoclasts lining metastatic bone surfaces in close contact to tumor cells. No difference in bone remodeling activity was seen between treatment-naïve and castration-resistant patients, while the bone remodeling activity was inversely correlated to AR activity in metastasis tissue (measured as expression of the AR, FOXA1, HOXB13, KLK2, KLK3, NKX3-1, STEAP2, and TMPRSS2) and to patient serum PSA levels. Ontology analysis suggested enriched BMP signaling in metastases with high bone remodeling activity and, accordingly, BMP4 mRNA expression was significantly higher in bone metastases with than without ongoing bone formation, as determined from histologic evaluation of van Gieson-stained sections. In conclusion, we have observed diversities in bone remodeling activity among clinical samples of prostate cancer bone metastases that may be of importance when selecting therapy for patients with bone metastatic cancer, especially when bone-targeting therapies are considered. The importance of the BMP signaling system for the development of sclerotic metastasis lesion deserves further exploration. Citation Format: Erik Bovinder Ylitalo, Annika Nordstrand, Elin Thysell, Emma Jernberg, Sead Crnalic, Anders Widmark, Anders Bergh, Ulf H. Lerner, Pernilla Wikström. Bone remodeling in relation to androgen receptor activity in prostate cancer bone metastases [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A048.

Abstract B5: Epigenetic modification of AR in PC3 cells negatively regulates mTORC1/2 activity

Abstract Wild type androgen receptor (AR) acts as a tumor suppressor and mediates the differentiation of non-malignant prostate epithelial cells. However, in the development of prostate cancer AR activity becomes critical for the development and progression of disease. Previous studies demonstrate that re-expressing wild type AR within an AR negative cell line (PC3) possesses tumor suppressor quality by reducing cell proliferation and tumorgenicity in mice. Further, it is documented that acetylation of AR in non-malignant cells is a post-translational modification associated with increased transcriptional activity of AR, whereas acetylation of AR in tumor cells results in negative regulation of AR transcriptional activity. We therefor are seeking to investigate the regulation of re-expressed AR within PC3 cells by induced acetylation post HDAC inhibition. Our preliminary data reveals that sensitivity to HDAC inhibition is increased with the re-expression of AR in PC3 cells. Further, epigenetic modification of AR in this model negatively regulates mTORC1 and mTORC2 expression and activity, independent of AR transcriptional activity. Ongoing experiments are being conducted to investigate further the role of epigenetic post-translational modification of AR and its negative regulation of mTORC1/2 signaling. Citation Format: Leigh Ellis, Remi Adelaiye, Shengyu Ku, Alejandro Godoy, Roberto Pili. Epigenetic modification of AR in PC3 cells negatively regulates mTORC1/2 activity [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr B5.

Abstract B58: hnRNP H1, a novel coactivator of the androgen receptor implicated in progression and hormone resistance of prostate cancer in African Americans

Abstract The causes of ethnic disparity in the clinical manifestation and outcome of prostate cancer (CaP) are not well understood. African Americans (AA) have twice the incidence and mortality of CaP than Caucasian Americans (CA). We identified by a novel functional genomics approach, encompassing laser capture microdissection (LCM), suppressive subtractive hybridization (SSH) and custom race-based CaPspecific cDNA array chips, selective expression of heterogeneous nuclear ribonucleoprotein H1 (hnRNP H1) in prostate tumor cells of AA in comparison to CA men. hnRNP H1 expression correlates with disease progression and score and poor prognosis in AA men. Subsequent functional studies demonstrate that hnRNP H1 up-regulates transcription, and physically interacts with, and confers hormone-dependent and independent transactivation of androgen receptor (AR) in CaP cells. In addition, hnRNP H1 enhances AR binding to its cognate DNA element on promoter and enhancer element of PSA gene and selective exonic domains of the AR gene. These findings support a model in which hnRNP H1 is an auxiliary coactivator for ligand-dependent and independent transactivation of AR in tumor cells. Furthermore, siRNA silencing of hnRNP H1 elicited growth arrest and enhanced cytotoxicity of antiandrogen bicalutamide in CaP cells. Our data support a new role for hnRNP H1 in ethnic disparity of CaP and further demonstrate a previously uncharacterized mechanism for AR-hnRNP H1 axis in disease progression and development of hormone refractory in AA men. Citation Information: Cancer Epidemiol Biomarkers Prev 2010;19(10 Suppl):B58.

Personalized Prediction of Tumor Response and Cancer Progression on Prostate Needle Biopsy

To our knowledge in patients with prostate cancer there are no available tests except clinical variables to determine the likelihood of disease progression. We developed a patient specific, biology driven tool to predict outcome at diagnosis. We also investigated whether biopsy androgen receptor levels predict a durable response to therapy after secondary treatment. We evaluated paraffin embedded prostate needle biopsy tissue from 1,027 patients with cT1c-T3 prostate cancer treated with surgery and followed a median of 8 years. Machine learning was done to integrate clinical data with biopsy quantitative biometric features. Multivariate models were constructed to predict disease progression with the C index to estimate performance. In a training set of 686 patients (total of 87 progression events) 3 clinical and 3 biopsy tissue characteristics were identified to predict clinical progression within 8 years after prostatectomy with 78% sensitivity, 69% specificity, a C index of 0.74 and a HR of 5.12. Validation in an independent cohort of 341 patients (total of 44 progression events) yielded 76% sensitivity, 64% specificity, a C index of 0.73 and a HR of 3.47. Increased androgen receptor in tumor cells in the biopsy highly significantly predicted resistance to therapy, ie androgen ablation with or without salvage radiotherapy, and clinical failure (p <0.0001). Morphometry reliably classifies Gleason pattern 3 tumors. When combined with biomarker data, it adds to the hematoxylin and eosin analysis, and prostate specific antigen values currently used to assess outcome at diagnosis. Biopsy androgen receptor levels predict the likelihood of a response to therapy after recurrence and may guide future treatment decisions.