Aberrant activities of various cell cycle and DNA repair
proteins promote
cancer growth and progression and render them resistant to
therapies. Here, we demonstrate that the anti-depressant
imipramine blocks growth of triple-negative (TNBC) and
estrogen receptor-positive (ER+) breast
cancers by inducing cell cycle arrest and by blocking heightened homologous recombination (HR) and non-homologous end joining-mediated (NHEJ) DNA repair activities. Our results reveal that
imipramine inhibits the expression of several cell cycle- and DNA repair-associated
proteins including E2F1, CDK1,
Cyclin D1, and RAD51. In addition, we show that
imipramine inhibits the growth of ER + breast
cancers by inhibiting the
estrogen receptor- α (ER-α) signaling. Our studies in preclinical mouse models and ex vivo explants from
breast cancer patients show that
imipramine sensitizes TNBC to the
PARP inhibitor olaparib and endocrine resistant ER + breast
cancer to anti-
estrogens. Our studies suggest that repurposing
imipramine could enhance routine care for
breast cancer patients. Based on these results, we designed an ongoing clinical trial, where we are testing the efficacy of
imipramine for treating patients with triple-negative and
estrogen receptor-positive
breast cancer. Since aberrant DNA repair activity is used by many
cancers to survive and become resistant to
therapy,
imipramine could be used alone and/or with currently used drugs for treating many aggressive
cancers.