Wnt signaling regulates a variety of cellular processes, including cell fate, differentiation, proliferation and stem cell pluripotency. Aberrant Wnt signaling is a hallmark of many cancers. An aggressive subtype of breast cancer, known as triple-negative breast cancer (TNBC), demonstrates dysregulation in canonical and non-canonical Wnt signaling. In this review, we summarize regulators of canonical and non-canonical Wnt signaling, as well as Wnt signaling dysfunction that mediates the progression of TNBC. We review the complex molecular nature of TNBC and the emerging therapies that are currently under investigation for the treatment of this disease.

Wnt signaling pathways are of significant interest in development and oncogenesis. The first step in these pathways typically involves the binding of a Wnt protein to the cysteine-rich domain (CRD) of a Frizzled receptor. Wnt-Frizzled interactions can be antagonized by secreted Frizzled-related proteins (SFRPs), which also contain a Frizzled-like CRD. The large number of Wnts, Frizzleds, and SFRPs, as well as the hydrophobic nature of Wnt, poses challenges to laboratory-based investigations of interactions involving Wnt. Here, utilizing structural knowledge of a representative Wnt-Frizzled CRD interaction, as well as experimentally determined binding affinities for a selection of Wnt-Frizzled CRD interactions, we generated homology models of Wnt-Frizzled CRD interactions and developed a quantitative structure-activity relationship for predicting their binding affinities. The derived model incorporates a small selection of terms derived from scoring functions used in protein-protein docking, as well as an energetic term considering the contribution made by the lipid of Wnt to the Wnt-Frizzled binding affinity. Validation with an external test set suggests that the model can accurately predict binding affinity for 75% of cases and that the error associated with the predictions is comparable with the experimental error. The model was applied to predict the binding affinities of the full range of mouse and human Wnt-Frizzled and Wnt-SFRP interactions, indicating trends in Wnt binding affinity for Frizzled and SFRP CRDs. The comprehensive predictions made in this study provide the basis for laboratory-based studies of previously unexplored Wnt-Frizzled and Wnt-SFRP interactions, which, in turn, may reveal further Wnt signaling pathways.

Significance: B cell lymphoma-2 (Bcl-2) was discovered over three decades ago and is the prototype antiapoptotic member of the Bcl-2 family that comprises proteins with contrasting effects on cell fate. First identified as a consequence of chromosomal translocation (t 14:18) in human lymphoma, subsequent studies have revealed mutations and/or gene copy number alterations as well as post-translational modifications of Bcl-2 in a variety of human cancers. The canonical function of Bcl-2 is linked to its ability to inhibit mitochondrial membrane permeabilization, thereby regulating apoptosome assembly and activation by blocking the cytosolic translocation of death amplification factors. Of note, the identification of specific domains within the Bcl-2 family of proteins (Bcl-2 homology domains; BH domains) has not only provided a mechanistic insight into the various interactions between the member proteins but has also been the impetus behind the design and development of small molecule inhibitors and BH3 mimetics for clinical use. Recent Advances: Aside from its role in maintaining mitochondrial integrity, recent evidence provides testimony to a novel facet in the biology of Bcl-2 that involves an intricate cross talk with cellular redox state. Bcl-2 overexpression modulates mitochondrial redox metabolism to create a “pro-oxidant” milieu, conducive for cell survival. However, under states of oxidative stress, overexpression of Bcl-2 functions as a redox sink to prevent excessive buildup of reactive oxygen species, thereby inhibiting execution signals. Emerging evidence indicates various redox-dependent transcriptional changes and post-translational modifications with different functional outcomes. Critical Issues: Understanding the complex interplay between Bcl-2 and the cellular redox milieu from the standpoint of cell fate signaling remains vital for a better understanding of pathological states associated with altered redox metabolism and/or aberrant Bcl-2 expression. Future Directions: Based on its canonical functions, Bcl-2 has emerged as a potential druggable target. Small molecule inhibitors of Bcl-2 and/or other family members with similar function, as well as BH3 mimetics, are showing promise in the clinic. The emerging evidence for the noncanonical activity linked to cellular redox metabolism provides a novel avenue for the design and development of diagnostic and therapeutic strategies against cancers refractory to conventional chemotherapy by the overexpression of this prosurvival protein.