Purpose: Beyond testosterone, several steroids contribute to the activation of the androgen receptor pathway, but their relative contributions to the activation of the androgen receptor signaling axis in patients with castrated prostate cancer remain unknown.
Materials And Methods: Serum levels of 9 steroids were measured by mass spectrometry from continuously castrated patients of the PR.7 study (219) and from the PCA24 cohort (116). For each steroid standard curves for dose dependent prostate specific antigen promoter activation were built in castration sensitive (LAPC4) and resistant (VCaP) prostate cancer models. Standard curves were used to determine the androgen receptor activation potency for each steroid measurement from patients in these trials.
Results: In LAPC4 and VCaP cells testosterone, dihydrotestosterone and androstenedione induced androgen receptor transcriptional activity, while dehydroepiandrosterone, 5alpha-androstan-3beta,17beta-diol, androstenediol and androsterone stimulated androgen receptor only in VCaP cells. Extragonadal steroids were responsible for 34% (LAPC4) and 88% (VCaP) of the serum total androgen receptor transcriptional activity found in castrated cases. The total androgen receptor transcriptional activity secondary to testosterone, dihydrotestosterone and androstenedione was associated with time to castration resistance in patients from the PR.7 study (HR 2.17, 95% CI 1.12-4.23, p=0.02) in multivariate analysis using the castration sensitive model (LAPC4). Androgen receptor transcriptional activity of extragonadal androstenedione was the only steroid statistically associated with time to castration resistance in univariate analysis (HR 1.89, 95% CI 1.04-3.44, p=0.036).
Conclusions: Extragonadal steroids contribute significantly to the androgen receptor axis activation at castration levels of testosterone in recurrent nonmetastatic prostate cancer and these sustain the development of castration resistance after primary local treatment.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1097/JU.0000000000000699 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Beyond the Horizon: Rethinking Prostate Cancer Treatment Through Innovation and Alternative Strategies.
Cancers (Basel)
December 2024
Department of Biochemistry and Molecular Biology, LSU Health Shreveport, Shreveport, LA 71103, USA.
For nearly a century, fundamental observations that prostate cancer (PCa) cells nearly always require AR stimulation for sustained proliferation have led to a unidirectional quest to abrogate such a pathway. Similarly focused have been efforts to understand AR-driven processes in the context of elevated expression of its target genes, and much less so on products that become overexpressed when AR signaling is suppressed. Treatment with ARSI results in an increased expression of the TLK1B splice variant via a 'translational' derepression driven by the compensatory mTOR activation and consequent activation of the TLK1 > NEK1 > ATR > Chk1 and NEK1 > YAP axes.
View Article and Find Full Text PDFCost-Effectiveness of PARP Inhibitors for Patients with BRCA1/2-Positive Metastatic Castration-Resistant Prostate Cancer-The Canadian Perspective.
Cancers (Basel)
December 2024
Faculty of Pharmacy, University of Montreal, 2940 Chem. de Polytechnique, Montreal, QC H3T 1J4, Canada.
Background/objectives: Through phase III clinical trials, PARP inhibitors have demonstrated outcome improvements in mCRPC patients with alterations in BRCA1/2 genes who have progressed on a second-generation androgen receptor pathway inhibitor (ARPI). While improving outcomes, PARP inhibitors contribute to the ever-growing economic burden of PCa. The objective of this project is to evaluate the cost-effectiveness of PARP inhibitors (olaparib, rucaparib, or talazoparib) versus the SOC (docetaxel or androgen receptor pathway inhibitors (ARPI)) for previously progressed mCRPC patients with BRCA1/2 mutations from the Canadian healthcare system perspective.
View Article and Find Full Text PDFSpatial Genomics Identifies Heat Shock Proteins as Key Molecular Changes Associated to Adipose Periprostatic Space Invasion in Prostate Cancer.
Cancers (Basel)
December 2024
CeRePP, 75020 Paris, France.
Purpose: To identify molecular changes during PCa invasion of adipose space using Spatial Transcriptomic Profiling of PCa cells.
Methods: This study was performed on paired intraprostatic and extraprostatic samples obtained from radical prostatectomy with pT3a pathological stages.
Results: Differential gene expression revealed upregulation of heat shock protein genes: DNAJB1, HSPA8, HSP90AA1, HSPA1B, HSPA1A in PCa PanCK+ cells from the adipose periprostatic space.
Molecular Sentinels: Unveiling the Role of Sirtuins in Prostate Cancer Progression.
Int J Mol Sci
December 2024
Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA.
Prostate cancer (PCa) remains a critical global health challenge, with high mortality rates and significant heterogeneity, particularly in advanced stages. While early-stage PCa is often manageable with conventional treatments, metastatic PCa is notoriously resistant, highlighting an urgent need for precise biomarkers and innovative therapeutic strategies. This review focuses on the dualistic roles of sirtuins, a family of NAD+-dependent histone deacetylases, dissecting their unique contributions to tumor suppression or progression in PCa depending on the cellular context.
View Article and Find Full Text PDFDifferential Expression of CXCL12 in Human and Mouse Hair: Androgens Induce CXCL12 in Human Dermal Papilla and Dermal Sheath Cup.
Int J Mol Sci
December 2024
Epi Biotech Co., Ltd., Incheon 21983, Republic of Korea.
We previously demonstrated that C-X-C Motif Chemokine Ligand 12 (CXCL12) is primarily secreted by dermal fibroblasts in response to androgens and induces hair miniaturization in the mouse androgenic alopecia (AGA) model. However, the direct effects of androgen-induced CXCL12 on dermal papilla cells (DPCs) and dermal sheath cup cells (DSCs) have not been demonstrated. First, we compared single-cell RNA sequencing data between mouse and human skin, and the results show that CXCL12 is highly co-expressed with the androgen receptor (AR) in the DPCs and DSCs of only human hair.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!