FoxO3a mediates the inhibitory effects of the antiepileptic drug Lamotrigine on breast cancer growth

Breast cancer (BC) is a complex and heterogeneous disease, with distinct histological features dictating the therapy. Although the clinical outcome of BC 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 BC therapy are needed. As a "faster" alternative to reach this aim, we evaluated if Lamotrigine (LTG), a broadly used anticonvulsivant, could be "repurposed" as an antitumoral drug in BC. Our data show that LTG inhibits the proliferation, the anchorage-dependent and independent cell growth in BC cells (BCCs), including hormone-resistant cell models. These effects were associated with cell cycle arrest and modulation of related proteins (cyclin D1, cyclin E, p27Kip1 and p21Waf1/Cip1), all target genes of FoxO3a, an ubiquitous transcription factor negatively regulated by AKT. LTG 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, LTG induces FoxO3a expression by increasing its transcription through FoxO3a recruitment on specific FHRE located on its own promoter, in an autoregulatory fashion. Finally, LTG significantly reduced tumor growth in vivo, increasing FoxO3a expression.