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Multiple anti-tumor programs are activated by blocking BAD phosphorylation

Oncogene volume 44, pages 2530–2546 (2025)Cite this article

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Abstract

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-Bad3SA/3SA, 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 BAD3SA mutation unmasked latent anti-tumor activity. Indeed, transcriptomics showed PyMT-Bad3SA/3SA 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.

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Fig. 1: Bad3SA delays tumor progression in MMTV-PyMT breast cancer model.
Fig. 2: RNA-seq screen identifies molecular markers that are altered in PyMT-Bad3SA.
Fig. 3: PyMT-Bad3SA tumors are sensitized to apoptosis and are more functionally differentiated.
Fig. 4: PyMT-Bad3SA impedes breast cancer invasion and metastasis in vitro and in vivo.
Fig. 5: BAD phosphorylation is prognostic for breast cancer patient overall survival.
Fig. 6: BAD is phosphorylated via the MEK-ERK pathway.
Fig. 7: The ERK pathway is paramount for breast tumor invasion.

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Data availability

Uncropped raw blots underlying the figures are in Supplementary Table 4. RNA-seq raw paired-end sequencing reads (fastq format) and complete DESeq2 analysis are deposited in the Gene Expression Omnibus (GEO) public repository, accession GSE196626. Main functions, packages, and modules used in MATLAB(version R2022a/b), R(version 4.2.2), and Python (version 3.9,) respectively, as well as bi-directional communication and data exchange between MATLAB and R are detailed in the ‘Methods’ and Supplementary File 1. Detailed custom codes and their dependency to reproduce the data are included in Supplementary File 1.

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Acknowledgements

We are grateful to all Goping lab members for their valuable discussions and contributions. We thank Dr. Kristi Baker for the generous gift of anti-CD8 antibody. Cell Imaging Core Experiments were performed at the University of Alberta Faculty of Medicine & Dentistry Cell Imaging Core, RRID:SCR_019200, which receives financial support from the Faculty of Medicine & Dentistry, the University Hospital Foundation, Striving for Pandemic Preparedness – The Alberta Research Consortium, and Canada Foundation for Innovation (CFI) awards to contributing investigators. The authors acknowledge the dedicated support and expertise provided by the North Campus Animal Services (NCAS) staff and veterinarians. This work was supported by operating grants from the Alberta Cancer Foundation and Canadian Institutes of Health Research to ISG. ISG gratefully acknowledges support as the Lilian McCullough Chair in Breast Cancer Research.

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Authors and Affiliations

  1. Department of Biochemistry, University of Alberta, Edmonton, AB, Canada

    John Maringa Githaka, Raven Kirschenman, Namrata Patel, Namita Tripathi, Joy Wang, Laiji Li, Heather Muranyi, Leila Pirayeshfard, Rachel Montpetit & Ing Swie Goping

  2. Department of Oncology, University of Alberta, Edmonton, AB, Canada

    Darryl D. Glubrecht, Roseline Godbout & Ing Swie Goping

  3. Department of Surgery, University of Alberta, Edmonton, AB, Canada

    E. Paul Lerner & Troy Perry

  4. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA

    Nika N. Danial

  5. Animal Pathology Services (APS) Ltd., Canmore, AB, Canada

    P. Nick Nation

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Contributions

I.S.G. conceived the study. J.M.G., R.K., N.P., and I.S.G. designed the research. J.M.G., R.K., N.T., J.W., H.M., N.T., L.P., E.P.L., T.P., and R.M. performed the experiments. N.D. provided mouse strains. J.M.G., N.P., P.N.N., and J.W. analyzed the data. I.S.G. directed research. J.M.G. and I.S.G. wrote the paper.

Corresponding authors

Correspondence to John Maringa Githaka or Ing Swie Goping.

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The authors declare no competing interests.

Ethics approval

All mouse experiments and procedures were performed in accordance with the guidelines and regulations set forth by the Canadian Council on Animal Care and approved by the University of Alberta Health Sciences Animal Care and Use Committee (Protocol# AUP00000386).

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Githaka, J.M., Kirschenman, R., Patel, N. et al. Multiple anti-tumor programs are activated by blocking BAD phosphorylation. Oncogene 44, 2530–2546 (2025). https://doi.org/10.1038/s41388-025-03420-1

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