pSTAT3 Expression is Increased in Advanced Prostate Cancer in Post-Initiation of Androgen Deprivation Therapy

Piotr Bialas; Tamae Kobayashi; Rebecka Hellsten; Agnieszka Krzyzanowska; Margareta Persson; Felicia Marginean; Dominique Trudel; Isla P Garraway; Bruce J Trock; Pekka Taimen; Fred Saad; Tuomas Mirtti; Beatrice Knudsen; Angelo M De Marzo; Anders Bjartell

doi:10.1002/pros.24820

pSTAT3 Expression is Increased in Advanced Prostate Cancer in Post-Initiation of Androgen Deprivation Therapy

Prostate. 2024 Nov 11. doi: 10.1002/pros.24820. Online ahead of print.

Authors

Piotr Bialas^{1

2}, Tamae Kobayashi¹, Rebecka Hellsten¹, Agnieszka Krzyzanowska¹, Margareta Persson³, Felicia Marginean¹, Dominique Trudel^{4

5}, Isla P Garraway^{6

7}, Bruce J Trock⁸, Pekka Taimen^{9

10}, Fred Saad¹¹, Tuomas Mirtti^{12

13}, Beatrice Knudsen¹⁴, Angelo M De Marzo^{8

15

16}, Anders Bjartell^{1

17}

Affiliations

¹ Department of Translational Medicine, Division of Urological Cancers, Lund University, Malmö, Sweden.
² Chair and Department of Cell Biology, Poznan University of Medical Sciences, Poznan, Poland.
³ Department of Laboratory Medicine, Translational Cancer Research, Lund University, Lund, Sweden.
⁴ Centre de recherche du Centre hospitalier de l'Université de Montréal et Institut du cancer de Montréal, Montreal, Quebec, Canada.
⁵ Department of Pathology and Cellular Biology, Université de Montréal, Montreal, Quebec, Canada.
⁶ Department of Urology, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California, Los Angeles, California, USA.
⁷ Division of Urology, Greater Los Angeles VA Healthcare System, Los Angeles, California, USA.
⁸ Department of Urology and Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
⁹ Institute of Biomedicine and FICAN West Cancer Centre, University of Turku, Turku, Finland.
¹⁰ Department of Pathology, Turku University Hospital, Turku, Finland.
¹¹ Department of Surgery, Université de Montréal, Montreal, Quebec, Canada.
¹² HUS Diagnostic Center, Department of Pathology, HUS Helsinki University Hospital, Helsinki, Finland.
¹³ Medicum and Research Program In Systems Oncology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
¹⁴ Digital and Computational Pathology, University of Utah, Salt Lake City, Utah, USA.
¹⁵ Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
¹⁶ Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA.
¹⁷ Department of Urology, Skåne University Hospital, Malmö, Sweden.

PMID: 39523927
DOI: 10.1002/pros.24820

Abstract

Background: The transcription factor Signal Transducer and Activator of Transcription 3 (STAT3) plays a role in carcinogenesis and is involved in processes, such as proliferation, differentiation, drug resistance and immunosuppression. STAT3 can be activated by phosphorylation of tyrosine at position 705 (pSTAT3^Tyr705) or serine at 727 (pSTAT3^Ser727). High expression levels of pSTAT3 are implicated in advanced stages of prostate cancer (PCa) and are known to interact with the androgen receptor signaling pathway. However, not much is known about how androgen deprivation therapy (ADT) in advanced disease affects pSTAT3 expression. The aim of this study was to determine the influence of ADT on pSTAT3 expression in PCa tissue.

Methods: The study cohort came from a PCa tissue microarray resource containing prostate specimens from patients before and post-initiation of ADT. Tissue samples from 111 patients were immunostained for pSTAT3^Tyr705 and pSTAT3^Ser727. H-score was used to evaluate the intensity and the percentage of pSTAT3 expression in malignant epithelial and stromal compartments. Univariate and multivariable Cox regression analyses were used to assess pSTAT3^Tyr705 and pSTAT3^Ser727 as biomarkers of oncological outcome in patients undergoing ADT.

Results: Post-ADT PCa samples demonstrated increased nuclear and cytoplasmic levels of pSTAT3^Ser727 in the stroma compared to pre-ADT samples, whereas pSTAT3^Tyr705 expression was increased significantly in both stromal and malignant epithelial compartments except for stromal cytoplasm. High cytoplasmic pSTAT3^Ser727 in stromal compartments correlated with reduced overall survival, shorter time to castration-resistant PCa development, and decreased metastasis-free survival. An increase in nuclear and cytoplasmic pSTAT3^Ser727 expression within the stromal compartment of post-ADT samples corresponded to a shorter time to CRPC development, which was not observed for pSTAT3^Tyr705. Multivariable survival analysis using Cox's regression identified that high cytoplasmic pSTAT3^Ser727 expression in the stroma of post-ADT samples and pT3 or pT4-stage were associated with worse overall survival and 5-year metastasis-free survival (MFS).

Conclusions: This study presents novel insights into the impact of ADT on the expression levels of pSTAT3^Tyr705 and pSTAT3^Ser727 in PCa. Cytoplasmic pSTAT3^Ser727 status of cancer-associated stromal cells in post-ADT samples may serve as an independent prognostic marker for OS and 5-year MFS, identifying prostate cancer patients prone to developing resistance to ADT.

Keywords: STAT3; androgen deprivation therapy; androgens; biomarkers; prostate cancer.

Grants and funding

This work was supported by Swedish Scientific Council, ALF Lund University, Kungliga Fysiografiska Sallskapet i Lund, Movember Foundation, NIH/NCI SPORE, Fonds de Recherche du Québec-Santé and Swedish Cancer Foundation.