Overexpression of 14-3-3ζ has been observed in numerous human cancers, including those of the esophagus, breast, lung, brain, and prostate [
12,
15]. More recently, 14-3-3ζ has been detected in the secretomes produced by these cancers, suggesting that monitoring 14-3-3ζ expression may serve as a potential prognostic biomarker for late-stage breast carcinomas [
9,
14]. Equally intriguing is the finding by Xu et al. that 14-3-3ζ is capable of dictating the expression patterns of additional 14-3-3 family members (e.g., 14-3-3σ), thereby generating an extensive level of control capable of fine-tuning the context and pathological output of metastatic signals stimulated by TGF-β. Accordingly, Boudreau et al. [
16] demonstrated that 14-3-3σ, which typically functions as a tumor suppressor, may in fact enhance the invasive behaviors of basal-like breast cancer cells, doing so by regulating cytoskeletal dynamics in a protein kinase Cζ-dependent manner. In both studies, aberrant 14-3-3 family member activity was associated with basal-like and triple-negative breast cancers (TNBCs), both of which respond to the tumor-promoting activities of TGF-β. It should be noted that basal-like/TNBCs are generally not highly metastatic to bone and instead preferentially metastasize to visceral organs and the brain [
17], which contrasts sharply with their estrogen receptor alpha-positive counterparts that do in fact preferentially metastasize to bone and are responsive to the tumor-suppressing activities of TGF-β [
18,
19]. Future studies need to: (1) identify which specific basal-like/TNBC subtypes are dependent upon dysregulated 14-3-3 family and oncogenic TGF-β signaling; (2) establish the impact of aberrant 14-3-3 family member expression in non-TNBC subtypes, as well as their response to TGF-β; and (3) demonstrate a causal role of dysregulated 14-3-3 family expression in dictating breast cancer dissemination to organ sites other than bone.
Finally, it is interesting to note that the activities associated with aberrant 14-3-3ζ expression are highly reminiscent of those attributed to the oncogenic functions of TGF-β, including the ability to drive carcinoma cell proliferation, survival, and chemoresistance [
1,
2,
9]. The highlighted work by Xu et al. implicates 14-3-3ζ as a prominent player that dictates the pathophysiology of canonical TGF-β signaling in neoplastic cells. However, TGF-β also activates numerous noncanonical signaling effectors that are equally essential in mediating the tumor-promoting functions of TGF-β in developing and progressing breast cancers [
4]. Future studies thus clearly need to expand our understanding of the role of 14-3-3 family members in eliciting metastatic progression driven by TGF-β, particularly with respect to determining the extent to which (1) aberrant 14-3-3ζ expression engages the noncanonical TGF-β signaling system, (2) noncanonical TGF-β effectors engender dysregulated expression of 14-3-3ζ, and (3) aberrant 14-3-3ζ expression can be targeted therapeutically and/or utilized as a predictive biomarker to delineate breast cancer patients most likely to respond to anti-TGF-β agents. Ultimately, answering these and other questions will provide a foundation to develop more effective therapies against the oncogenic functions of TGF-β and its stimulation of breast cancer metastasis.