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

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.

Keywords: GTPase; distant metastasis-free survival (DMFS); estrogen receptor (ER); guanylate-binding protein (GBP); interferon-γ (IFN-γ); overall survival (OS); progesterone receptor (PR); recurrence-free survival (RFS); signal transducer and activator of transcription 1 (STAT1); triple negative breast cancer (TNBC).

Figure 1

High levels of GBP-1 correlate with better recurrence-free (RFS), overall survival (OS), and distance metastasis-free survival (DMFS) in human ER− and TNBC breast cancers. Km plots were performed for RFS for those tumors with high versus low levels of GBP-1 expression for (A) all breast cancers, (B) ER− breast cancers, and (C) TNBCs. Km plots were performed for OS of tumors with high versus low GBP-1 expression for (D) all breast cancers, (E) ER− breast cancers, and (F) TNBCs. Km plots were performed for DMFS for those tumors with high versus low GBP-1 expression for (G) all breast cancers, (H) ER− breast cancers, and (I) TNBCs.

Figure 2

GBP-5 correlates with better recurrence-free (RFS) and overall survival (OS) in all breast cancers. The probability of RFS versus time for breast cancers of all types, stages, and grades was plotted for those tumors with high and low levels of GBP-5 expression (A). The probability of RFS versus time was plotted for ER−, PR−, and HER2− (TNBC) breast cancers for high versus low levels of GBP-5 expression (B,C). The OS of patients of patients with all subtypes, stages, and grades was plotted for those tumors with high versus low GBP-5 expression versus time (D). The probability of OS versus time was plotted for ER−, PR−, and HER2− (TNBC) breast cancers for high versus low levels of GBP-5 expression (E,F). The DMFS of patients of patients with all subtypes, stages, and grades was plotted for those tumors with high versus low GBP-5 expression versus time (G). The probability of DMFS versus time was plotted for ER−, PR−, and HER2− (TNBC) breast cancers for high versus low levels of GBP-5 expression (H,I).

Figure 3

GBP-2 correlates with better recurrence-free (RFS), overall survival (OS), and Distance Metastasis-free Survival (DMFS) in a cohort containing all breast cancers. The probability of RFS versus time for breast cancers of all types, stages, and grades was plotted for those tumors with high and low levels of GBP-2 expression (A). The probability of RFS versus time was plotted for ER−, PR−, and HER2− (TNBC) breast cancers for high versus low levels of GBP-2 expression (B,C). The OS of patients of patients with all subtypes, stages, and grades was plotted for those tumors with high versus low GBP-2 expression versus time (D). The probability of OS versus time was plotted for ER−, PR−, and HER2− (TNBC) breast cancers for high versus low levels of GBP-2 expression (E,F). The DMFS of patients of patients with all subtypes, stages, and grades was plotted for those tumors with high versus low GBP-2 expression versus time (G). The probability of DMFS versus time was plotted for ER−, PR−, and HER2− (TNBC) breast cancers for high versus low levels of GBP-2 expression (H,I).