Unraveling the Role of Guanylate-Binding Proteins (GBPs) in Breast Cancer: A Comprehensive Literature Review and New Data on Prognosis in Breast Cancer Subtypes

SIMPLE SUMMARY: Interferons are important in normal breast development, but also in the development and progression of breast cancers. Recently, three members of the Guanylate-Binding Protein (GBP) family of interferon-induced GTPases, GBP-1, GBP-2, and GBP-5, have been implicated to play roles in breast cancer. Both GBP-1 and GBP-5 are suggested to be potential drug targets in breast cancers, despite that there is no consensus on whether they are associated with better or worse prognoses. In fact, most of the literature related to GBPs in breast cancer suggests their expression correlates with improved prognoses. This manuscript will identify some of the reasons for this lack of consensus. ABSTRACT: At least one member of the Guanylate-Binding Protein (GBP) family of large interferon-induced GTPases has been classified as both a marker of good prognosis and as a potential drug target to treat breast cancers. However, the activity of individual GBPs appears to not just be tumor cell type–specific but dependent on the growth factor and/or cytokine environment in which the tumor cells reside. To clarify what we do and do not know about GBPs in breast cancer, the current literature on GBP-1, GBP-2, and GBP-5 in breast cancer has been assembled. In addition, we have analyzed the role of each of these GBPs in predicting recurrence-free survival (RFS), overall survival (OS), and distance metastasis-free survival (DMFS) as single gene products in different subtypes of breast cancers. When a large cohort of breast cancers of all types and stages were examined, GBP-1 correlated with poor RFS. However, it was the only GBP to do so. When smaller cohorts of breast cancer subtypes grouped into ER+, ER+/HER2−, and HER2+ tumors were analyzed, none of the GBPs influenced RFS, OS, or DMSF as single agents. The exception is GBP-5, which correlated with improved RFS in HER2+ breast cancers. All three GBPs individually predicted improved RFS, OS, and DMSF in ER− breast cancers, regardless of the PR or HER2 status, and TNBCs.