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Extragonadal Steroids Contribute Significantly to the Androgen Receptor Activity and Castration Resistance Development in Recurrent Prostate Cancers after Primary Therapy.
J Urol 2019; :101097JU0000000000000699JU

Abstract

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 signalling axis in castrated prostate cancer patients remain unknown.

MATERIALS AND METHODS

Serum levels of nine steroids were measured by mass spectrometry from continuously castrated patients of the PR.7 study (n=219) and from the PCA24 cohort (n=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 the above trials.

RESULTS

In LAPC4 and VCaP cells, testosterone, dihydrotestosterone and androstenedione induced androgen receptor transcriptional activity, while dehydroepiandrosterone, 5alpha-androstan-3beta,17beta-diol, androstenediol, 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 patients. 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 testosterone castration levels in recurrent non-metastatic prostate cancer and these sustain the development of castration resistance after primary local treatment.

Authors+Show Affiliations

Division of Urology, Department of Surgery and Cancer Research Center, Centre Hospitalier Universitaire (CHU) de Québec-Université Laval, Québec, QC, Canada.Division of Urology, Department of Surgery and Cancer Research Center, Centre Hospitalier Universitaire (CHU) de Québec-Université Laval, Québec, QC, Canada.Division of Urology, Department of Surgery and Cancer Research Center, Centre Hospitalier Universitaire (CHU) de Québec-Université Laval, Québec, QC, Canada.Division of Urology, Department of Surgery and Cancer Research Center, Centre Hospitalier Universitaire (CHU) de Québec-Université Laval, Québec, QC, Canada.Division of Urology, Department of Surgery and Cancer Research Center, Centre Hospitalier Universitaire (CHU) de Québec-Université Laval, Québec, QC, Canada.Division of Urology, Department of Surgery and Cancer Research Center, Centre Hospitalier Universitaire (CHU) de Québec-Université Laval, Québec, QC, Canada.NCIC Clinical Trials Group, Queen's University, Kingston, ON, Canada.Pharmacy Faculty, Université Laval and CHU de Québec-Université Laval, Québec, QC, Canada.Division of Urology, Department of Surgery and Cancer Research Center, Centre Hospitalier Universitaire (CHU) de Québec-Université Laval, Québec, QC, Canada.Medicine Faculty, Université Laval and CHU de Québec-Université Laval, Québec, QC, Canada.Sunnybrook Health Sciences Centre (LK), University of Toronto, Toronto, ON, Canada.Pharmacy Faculty, Université Laval and CHU de Québec-Université Laval, Québec, QC, Canada.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31845837

Citation

Pouliot, Frédéric, et al. "Extragonadal Steroids Contribute Significantly to the Androgen Receptor Activity and Castration Resistance Development in Recurrent Prostate Cancers After Primary Therapy." The Journal of Urology, 2019, pp. 101097JU0000000000000699.
Pouliot F, Rouleau M, Neveu B, et al. Extragonadal Steroids Contribute Significantly to the Androgen Receptor Activity and Castration Resistance Development in Recurrent Prostate Cancers after Primary Therapy. J Urol. 2019.
Pouliot, F., Rouleau, M., Neveu, B., Toren, P., Morin, F., Vélot, L., ... Guillemette, C. (2019). Extragonadal Steroids Contribute Significantly to the Androgen Receptor Activity and Castration Resistance Development in Recurrent Prostate Cancers after Primary Therapy. The Journal of Urology, pp. 101097JU0000000000000699. doi:10.1097/JU.0000000000000699.
Pouliot F, et al. Extragonadal Steroids Contribute Significantly to the Androgen Receptor Activity and Castration Resistance Development in Recurrent Prostate Cancers After Primary Therapy. J Urol. 2019 Dec 17;101097JU0000000000000699. PubMed PMID: 31845837.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Extragonadal Steroids Contribute Significantly to the Androgen Receptor Activity and Castration Resistance Development in Recurrent Prostate Cancers after Primary Therapy. AU - Pouliot,Frédéric, AU - Rouleau,Mélanie, AU - Neveu,Bertrand, AU - Toren,Paul, AU - Morin,Fannie, AU - Vélot,Lauriane, AU - Ding,Keyue, AU - Caron,Patrick, AU - Lacombe,Louis, AU - Lévesque,Éric, AU - Klotz,Laurence, AU - Guillemette,Chantal, Y1 - 2019/12/17/ PY - 2019/12/18/entrez KW - Androgen receptor activity KW - Bioluminescence KW - Mass spectrometry KW - Prostate cancer KW - Steroids SP - 101097JU0000000000000699 EP - 101097JU0000000000000699 JF - The Journal of urology JO - J. Urol. N2 - 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 signalling axis in castrated prostate cancer patients remain unknown. MATERIALS AND METHODS: Serum levels of nine steroids were measured by mass spectrometry from continuously castrated patients of the PR.7 study (n=219) and from the PCA24 cohort (n=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 the above trials. RESULTS: In LAPC4 and VCaP cells, testosterone, dihydrotestosterone and androstenedione induced androgen receptor transcriptional activity, while dehydroepiandrosterone, 5alpha-androstan-3beta,17beta-diol, androstenediol, 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 patients. 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 testosterone castration levels in recurrent non-metastatic prostate cancer and these sustain the development of castration resistance after primary local treatment. SN - 1527-3792 UR - https://www.unboundmedicine.com/medline/citation/31845837/Extragonadal_Steroids_Contribute_Significantly_to_the_Androgen_Receptor_Activity_and_Castration_Resistance_Development_in_Recurrent_Prostate_Cancers_after_Primary_Therapy L2 - https://www.jurology.com/doi/full/10.1097/JU.0000000000000699?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -