14-3-3ζ loss impedes oncogene-induced mammary tumorigenesis and metastasis by attenuating oncogenic signaling

The 14-3-3ζ protein belongs to the 14-3-3 family of regulatory eukaryotic proteins that modulate signaling by binding to wide variety of signaling molecules. 14-3-3ζ expression is amplified in over 40% breast cancer patients and is associated with a poor prognosis. Various in vitro and xenograft models have suggested that attenuating 14- 3-3ζ expression may provide therapeutic benefits but there has been no study looking at tumor onset and metastasis in breast cancer mouse models with a targeted deletion of 14-3-3ζ. We generated a 14-3-3ζ knockout mouse model to characterize the role of 14-3-3ζ in breast cancer progression. Crossing 14-3-3ζ-/- mice with MMTV-PyMT and MMTV-Neu transgenic mice revealed that loss of 14-3-3ζ prolonged tumor latency and reduced lung metastasis as compared to MMTV-PyMT and MMTV-Neu mice. Mechanistically, loss of 14-3-3ζ suppressed tumor proliferation and angiogenesis and promoted apoptosis by suppressing the Akt and Erk pathway and upregulated the expression of the tumor suppressor p53. Our results provide evidence showing that attenuating 14-3-3ζ expression/activity in mammary tumors can provide a therapeutic benefit.