Interplay between Caveolin-1 and body and tumor size affects clinical outcomes in breast cancer

Caveolin-1 (CAV1) is associated with cholesterol-rich membrane raft domains and is a master regulator of cell signaling and membrane transport. Here, we investigated CAV1's role in cellular compartments of breast cancer in relation to signaling pathways, clinicopathological features, and clinical outcomes.

CAV1 levels were evaluated with immunohistochemistry in cytoplasm of invasive tumor cells and stromal cells in tumor tissue microarrays from a cohort of 1018 breast cancer patients (inclusion 2002-2012, Sweden). Cytoplasmic and stromal CAV1 were categorized as positive/negative and strong/not strong, respectively. CAV1 expression in relation to clinical outcomes was assessed with Cox regression. Investigations into CAV1 functional pathways was conducted in the STRING, GOBO, and TCGA databases.

CAV1 expression was associated with non-luminal subtypes, cell cycle control, inflammation, epithelial-mesenchymal transition, and the IGF/Insulin system. Generally, CAV1 was not associated with recurrence risk. Stromal CAV1's impact on recurrence risk was modified by BMI ≥25 kg/m² (P_interaction = 0.002), waist ≥80 cm (P_interaction = 0.005), and invasive tumor size (pT2/3/4) (P_interaction = 0.028). In low-risk patients only, strong stromal CAV1 significantly increased recurrence risk (HRs_adj ≥1.61). In all patients, positive cytoplasmic CAV1 conferred >2-fold risk for contralateral disease HR_adj 2.63 (95% CI 1.36-5.10). Strong stromal CAV1 conferred nearly 2-fold risk for locoregional recurrence HR_adj 1.88 (95% CI 1.09-3.24).

CAV1's prognostic impact depended on its localization, anthropometric, and tumor factors. Stromal CAV1 predicted high recurrence risk in a group of supposedly 'low-risk' patients. Cytoplasmic CAV1 predicted metachronous contralateral disease. If confirmed, CAV1 could be used as treatment target and for risk-stratification.