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

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.

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.

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.

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