Augmenting hippocampal neurogenesis represents a potential new strategy for treating depression. Here we test this possibility by comparing hippocampal neurogenesis in depression-prone ghrelin receptor (Ghsr)-null mice to that in wild-type littermates and by determining the antidepressant efficacy of the P7C3 class of neuroprotective compounds. Exposure of Ghsr-null mice to chronic social defeat stress (CSDS) elicits more severe depressive-like behavior than in CSDS-exposed wild-type littermates, and exposure of Ghsr-null mice to 60% caloric restriction fails to elicit antidepressant-like behavior. CSDS resulted in more severely reduced cell proliferation and survival in the ventral dentate gyrus (DG) subgranular zone of Ghsr-null mice than in that of wild-type littermates. Also, caloric restriction increased apoptosis of DG subgranular zone cells in Ghsr-null mice, although it had the opposite effect in wild-type littermates. Systemic treatment with P7C3 during CSDS increased survival of proliferating DG cells, which ultimately developed into mature (NeuN+) neurons. Notably, P7C3 exerted a potent antidepressant-like effect in Ghsr-null mice exposed to either CSDS or caloric restriction, while the more highly active analog P7C3-A20 also exerted an antidepressant-like effect in wild-type littermates. Focal ablation of hippocampal stem cells with radiation eliminated this antidepressant effect, further attributing the P7C3 class antidepressant effect to its neuroprotective properties and resultant augmentation of hippocampal neurogenesis. Finally, P7C3-A20 demonstrated greater proneurogenic efficacy than a wide spectrum of currently marketed antidepressant drugs. Taken together, our data confirm the role of aberrant hippocampal neurogenesis in the etiology of depression and suggest that the neuroprotective P7C3-compounds represent a novel strategy for treating patients with this disease.

Background: Approximately 15% of breast cancers lack expression of Estrogen Receptor (ER), Progesterone Receptor (PR) and Human Epidermal Growth Factor Receptor 2 (HER-2), and are referred to as Triple Negative Breast Cancer (TNBC). Clinical outcomes in patients with TNBC continue to be poor due to inherently aggressive biology of the disease and paucity of targeted therapies. In this study, we identified Cell Division Cycle protein 20 (CDC20), a key regulatory protein that mediates sister chromatid separation in mitosis, as a novel therapeutic target in TNBC. Methods: To uncover new drivers of TNBC, we nominated genes that are significantly overexpressed in patients with TNBC, compared to non-TNBCs. After identifying CDC20 as a top hit in this analysis, we used expression microarrays, RNA-seq analyses and Western blotting to assess CDC20 expression levels in breast cancer patients and cell lines. Kaplan-Meier analyses were performed to study the correlation between CDC20 expression levels and clinical outcomes, including recurrence-free survival, metastasis-free survival and overall survival. shRNA-mediated knockdown of CDC20 in TNBC cell lines was employed to study the role of CDC20 in TNBC proliferation, invasion, migration and xenograft growth in mice. Results: CDC20 was significantly overexpressed in TNBCs (compared to non-TNBCs) in The Cancer Genome Atlas (TCGA) breast dataset, and in several other independent breast cancer datasets, including Curtis, Stickeler and Kao. CDC20 expression was also significantly higher in TNBC cell lines compared to non-TNBC cell lines. Furthermore, expression levels of CDC20 were highly significantly correlated with clinical outcomes, including recurrence-free survival, metastasis-free survival and overall survival. shRNA-mediated knockdown of CDC20 expression in TNBC cell lines, MDA-MB-231 and MDA-MB-468, resulted in decreased proliferation, invasion and migration. Our preliminary findings suggest that CDC20 knockdown also results in inhibition of cell line-derived xenograft growth in mice. Conclusion: We identified CDC20 is a novel therapeutic target in TNBC. Our findings support development of pharmacologic strategies to inhibit CDC20 function as a potential targeted therapy against TNBC. Citation Format: Sharma J, Raicu I, Nguyen J, Udden N, Wang Q, Alluri P. CDC20 is a novel therapeutic target in triple negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-06-20.