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. 2025 Jul 22.
doi: 10.1007/s10549-025-07786-4. Online ahead of print.

Higher pre-diagnostic serum syndecan-4 levels are associated with increased breast cancer risk: a case-cohort study

Endre Gabrielsen  1   2 , Tom Wilsgaard  3 , Hanne Frydenberg  4 , Trygve Lofterød  4 , Stig Manfred Dalen  5   6 , Elin Mortensen  5   6 , Marit D Solbu  7   8 , Hawa Nalwoga  9   10 , Lars A Akslen  9   11 , Egil S Blix #  7   12 , Hege S Haugnes #  7   12
Affiliations

Higher pre-diagnostic serum syndecan-4 levels are associated with increased breast cancer risk: a case-cohort study

Endre Gabrielsen et al. Breast Cancer Res Treat. .

Abstract

Purpose: Syndecans are transmembrane proteins involved in inflammation and signaling pathways. Their potential role as pre-diagnostic biomarkers for breast cancer risk remains unexplored. This study aimed to investigate whether pre-diagnostic serum syndecan levels are associated with breast cancer risk in a population-based cohort.

Methods: We conducted a case-cohort study nested within the Tromsø Study (Norway), including women who participated in the fifth survey (2001). Women with incident breast cancer (cases, n = 158) through 2022 were identified, with a random sub-cohort of 708 women. Serum levels of syndecan-1 (SDC1) and syndecan-4 (SDC4) were measured using ELISA on frozen serum samples obtained in 2001. All participants were stratified into quartiles (Q1-Q4) based on pre-diagnostic levels. Cox proportional hazards regression models assessed associations between serum syndecan levels and breast cancer risk.

Results: The median age at diagnosis was 69 years for cases, and 83.3% of tumors were hormone receptor-positive (HR +). Women with higher serum SDC4 (Q2-Q4) levels had approximately a twofold increased risk of breast cancer compared to women in Q1. We observed a nearly threefold increased risk for the HR + subtype. In postmenopausal women, HRs for HR + breast cancer in Q2, Q3, and Q4 were 3.81 (95% CI: 1.57-9.23), 3.43 (95% CI: 1.41-8.40), and 3.54 (95% CI: 1.45-8.65), respectively, all relative to Q1 of SDC4. No associations were observed between SDC1 levels and breast cancer risk.

Conclusions: Our results suggest that SDC4 may play a role in the initiation and early progression of breast cancer.

Keywords: Breast cancer; Case-cohort study; Hormone receptor-positive; Risk factors; Syndecan 1; Syndecan 4.

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Conflict of interest statement

Declarations. Competing interests: ESB: has received honoraria from AstraZeneca, Daiichi Sankyo, Eli Lilly, Novartis, Pfizer and Roche. HSH: has received honoraria from Merck, Janssen-Cilag, and Bayer. MDS: has received honoraria from AstraZeneca, Bayer, Boehringer-Ingelheim, and Vifor Pharma Other authors report no conflicts of interest. Ethical approval: The EBBA-life study has been approved by the Regional Committee for Medical and Health Research Ethics (REK) (2015/599). The Tromsø Study has been approved by REK (2014/940), Norwegian Data Protection Authority (14/01463–8/CGN September 07, 2015) and the Data Protection Impact Assessment (DPIA) (379273). Consent to participate: A declaration of consent was signed by all participants when enrolled in the Tromsø5 Study. Consent to publish: Not applicable, as no identifiable individual data are included in this study.

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