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- Godina, Christopher, et al.
(författare)
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Caveolin-1 gene expression provides additional prognostic information combined with PAM50 risk of recurrence (ROR) score in breast cancer
- 2024
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Combining information from the tumor microenvironment (TME) with PAM50 Risk of Recurrence (ROR) score could improve breast cancer prognostication. Caveolin-1 (CAV1) is a marker of an active TME. CAV1 is a membrane protein involved in cell signaling, extracellular matrix organization, and tumor-stroma interactions. We sought to investigate CAV1 gene expression in relation to PAM50 subtypes, ROR score, and their joint prognostic impact. CAV1 expression was compared between PAM50 subtypes and ROR categories in two cohorts (SCAN-B, n = 5326 and METABRIC, n = 1980). CAV1 expression was assessed in relation to clinical outcomes using Cox regression and adjusted for clinicopathological predictors. Effect modifications between CAV1 expression and ROR categories on clinical outcome were investigated using multiplicative and additive two-way interaction analyses. Differential gene expression and gene set enrichment analyses were applied to compare high and low expressing CAV1 tumors. All samples expressed CAV1 with the highest expression in the Normal-like subtype. Gene modules consistent with epithelial-mesenchymal transition (EMT), hypoxia, and stromal activation were associated with high CAV1 expression. CAV1 expression was inversely associated with ROR category. Interactions between CAV1 expression and ROR categories were observed in both cohorts. High expressing CAV1 tumors conferred worse prognosis only within the group classified as ROR high. ROR gave markedly different prognostic information depending on the underlying CAV1 expression. CAV1, a potential mediator between the malignant cells and TME, could be a useful biomarker that enhances and further refines PAM50 ROR risk stratification in patients with ROR high tumors and a potential therapeutic target.
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| 2. |
- Godina, Christopher
(författare)
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Metabolic and angiogenic biomarkers in breast cancer: potential clinical implications of host–tumor interactions
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Both caveolin-1 (CAV1) and insulin-like growth factor bindings protein 7 (IGFBP7) have been linked to angiogenesis, insulin-like growth factor (IGF) receptor 1 (IGF-1R) signaling, and the tumor microenvironment. However, CAV1 and IGFBP7 have not yet been adequately characterized and investigated as potential prognostic or treatment-predictive biomarkers at the genomic, transcriptomic, and proteomic level in breast cancer.Methods: CAV1 and IGFBP7 were investigated in two large prospective population-based cohorts: the Breast Cancer and Blood (BC-Blood) cohort and the Sweden Cancerome Analysis Network – Breast (SCAN-B) cohort, which both comprised early-stage breast cancer patients. Additionally, the roles of both CAV1 and IGFBP7 in breast cancer were explored in various public databases. IGFBP7 was further examined in the Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and Molecular Analysis 2 (I-SPY2), an adaptively randomized phase II clinical trial on neoadjuvant therapy for early-stage breast cancer.Results: In the BC-Blood cohort, the prognostic impact of CAV1 protein expression varied based on its localization, anthropometric factors, and tumor characteristics. Notably, CAV1 protein expression in malignant cells predicted a high incidence of breast cancer events among patients with tumors categorized as low-risk, while also indicating metachronous contralateral disease. Additionally, CAV1 polymorphisms were linked to an elevated risk of locoregional recurrence and contralateral breast cancer. On the other hand, low protein levels of tumor-specific IGFBP7 suggested a favorable prognosis. However, the prognostic significance of high levels of tumor-specific IGFBP7 depended on host factors and treatment. In the SCAN-B cohort, high CAV1 gene expression emerged as an independent prognostic factor in triple-negative breast cancer. Moreover, the molecular profile associated with high CAV1 gene expression implicated a potential role in chemoresistance and fostering a tumor-promoting tumor microenvironment. Similarly, elevated IGFBP7 gene expression was predictive of poor outcomes in breast cancer and correlated with a tumor-promoting tumor microenvironment. Conversely, low IGFBP7 gene expression identified a subset of breast cancer patients with a favorable response to ganitumab in the I-SPY2 trial.Conclusion: Both CAV1 and IGFBP7 have been identified as potential prognostic markers in breast cancer, although their significance may vary depending on the specific context. Notably, CAV1 appears to play a particularly crucial role in triple-negative breast cancer. Furthermore, the messenger ribonucleic acid (mRNA) expression of the IGFBP7 gene shows promise in predicting the efficacy of treatment targeting IGF-1R using monoclonal antibodies.
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