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

Christopher Godina; Vineesh Indira Chandran; Magdalena Barbachowska; Helga Tryggvadottir; Björn Nodin; Edward Visse; Signe Borgquist; Karin Jirström; Karolin Isaksson; Ana Bosch; Mattias Belting; Helena Jernström

doi:10.1016/j.tranon.2022.101464

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

Transl Oncol. 2022 Aug:22:101464. doi: 10.1016/j.tranon.2022.101464. Epub 2022 Jun 1.

Affiliations

¹ Division of Oncology, Department of Clinical Sciences in Lund, Lund University and Skåne University Hospital, Barngatan 4, Lund SE-221 85, Sweden.
² Division of Oncology, Department of Clinical Sciences in Lund, Lund University and Skåne University Hospital, Barngatan 4, Lund SE-221 85, Sweden; Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Sweden.
³ Division of Oncology and Therapeutic Pathology, Department of Clinical Sciences in Lund, Lund University and Skåne University Hospital, Lund, Sweden.
⁴ Division of Neurosurgery, Department of Clinical Sciences in Lund, Lund University and Skåne University Hospital, Lund, Sweden.
⁵ Division of Oncology, Department of Clinical Sciences in Lund, Lund University and Skåne University Hospital, Barngatan 4, Lund SE-221 85, Sweden; Department of Oncology, Aarhus University and Aarhus University Hospital, Aarhus, Denmark.
⁶ Division of Surgery, Department of Clinical Sciences in Lund, Lund University and Kristianstad Hospital, Kristianstad, Sweden.
⁷ Division of Oncology, Department of Clinical Sciences in Lund, Lund University and Skåne University Hospital, Barngatan 4, Lund SE-221 85, Sweden; Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Sweden; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
⁸ Division of Oncology, Department of Clinical Sciences in Lund, Lund University and Skåne University Hospital, Barngatan 4, Lund SE-221 85, Sweden. Electronic address: helena.jernstrom@med.lu.se.

Abstract

Background: 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.

Methods: 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.

Results: 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).

Conclusions: 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.

Keywords: Anthropometrics; Breast cancer; Caveolin-1; Cohort; Prognosis.