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- Godina, Christopher
(author)
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Metabolic and angiogenic biomarkers in breast cancer: potential clinical implications of host–tumor interactions
- 2024
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Doctoral thesis (other academic/artistic)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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