FoxO3a Mediates the Inhibitory Effects of the Antiepileptic Drug Lamotrigine on Breast Cancer Growth

Breast cancer is a complex and heterogeneous disease, with distinct histologic features dictating the therapy. Although the clinical outcome of breast cancer patients has been considerably improved, the occurrence of resistance to common endocrine and chemotherapy treatments remains the major cause of relapse and mortality. Thus, efforts in identifying new molecules to be employed in breast cancer therapy are needed. As a "faster" alternative to reach this aim, we evaluated whether lamotrigine, a broadly used anticonvulsant, could be "repurposed" as an antitumoral drug in breast cancer. Our data show that lamotrigine inhibits the proliferation, the anchorage-dependent, and independent cell growth in breast cancer cells (BCC), including hormone-resistant cell models. These effects were associated with cell-cycle arrest and modulation of related proteins (cyclin D1, cyclin E, p27^Kip1, and p21^Waf1/Cip1), all target genes of FoxO3a, an ubiquitous transcription factor negatively regulated by AKT. Lamotrigine also increases the expression of another FoxO3a target, PTEN, which, in turn, downregulates the PI3K/Akt signaling pathway, with consequent dephosphorylation, thus activation, of FoxO3a. Moreover, lamotrigine induces FoxO3a expression by increasing its transcription through FoxO3a recruitment on specific FHRE located on its own promoter, in an autoregulatory fashion. Finally, lamotrigine significantly reduced tumor growth in vivo, increasing FoxO3a expression.

Implications: The anticonvulsant drug lamotrigine shows strong antiproliferative activity on breast cancer, both in vitro and in vivo. Thus, drug repurposing could represent a valuable option for a molecularly targeted therapy in breast cancer patients. Mol Cancer Res; 16(6); 923–34. ©2018 AACR.

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