Methyl-CpG binding domain protein 2 (Mbd2) drives breast cancer progression through the modulation of...

Methyl-CpG-binding domain protein 2 (Mbd2), a reader of DNA methylation, has been implicated in different types of malignancies, including breast cancer. However, the exact role of Mbd2 in various stages of breast cancer growth and progression in vivo has not been determined. To test whether Mbd2 plays a causal role in mammary tumor growth and metastasis, we performed genetic knockout (KO) of Mbd2 in MMTV-PyMT transgenic mice and compared mammary tumor progression kinetics between the wild-type (PyMT-Mbd2^+/+) and KO (PyMT-Mbd2^-/-) groups. Our results demonstrated that deletion of Mbd2 in PyMT mice impedes primary tumor growth and lung metastasis at the experimental endpoint (postnatal week 20). Transcriptomic and proteomic analyses of primary tumors revealed that Mbd2 deletion abrogates the expression of several key determinants involved in epithelial-to-mesenchymal transition, such as neural cadherin (N-cadherin) and osteopontin. Importantly, loss of the Mbd2 gene impairs the activation of the PI3K/AKT pathway, which is required for PyMT-mediated oncogenic transformation, growth, and survival of breast tumor cells. Taken together, the results of this study provide a rationale for further development of epigenetic therapies targeting Mbd2 to inhibit the progression of breast cancer.