Multiple anti-tumor programs are activated by blocking BAD phosphorylation.

The Bcl-2 family member BAD is a candidate disease modulator because it stimulates apoptosis in a cell context basis and inhibits cell migration during normal mammary gland morphogenesis. This activity depends on 3 key regulatory serines (S75, 99, 118) in the unphosphorylated state. Given that developmental programs are often hijacked in cancer, we hypothesized that BAD would impede breast cancer progression. We generated breast cancer mouse models representing loss-of-function or phosphorylation deficient mutations (PyMT-Bad and PyMT-Bad, respectively). Preventing BAD phosphorylation significantly decreased breast cancer progression and metastasis. The knock-out phenocopied the control PyMT-Bad suggesting that phosphorylated BAD protein was inert. Thus, the BAD mutation unmasked latent anti-tumor activity. Indeed, transcriptomics showed PyMT-Bad activated multiple anti-tumor programs including apoptosis, inflammation, cellular differentiation, and diminished cell migration. This anti-tumor effect associated with clinical survival of breast cancer patients whose tumors had high levels of unphosphorylated BAD. Kinase screens identified ERK as the major BAD kinase in breast cells, and ERK inhibition impeded tumoroid invasion. Our data suggest that unphosphorylated BAD modulates anti-tumor pathways that contribute to excellent patient prognosis. Thus, targeting ERK to dephosphorylate BAD may be an exciting therapeutic opportunity in the future.