Breast cancer (BC) is the most common cancer and the second leading cause of cancer death in American women. About 10-20% of breast cancers are triple-negative breast cancer (TNBC), which has a propensity to metastasize, recur, and develop resistance to chemotherapy. TNBC is the only subtype of BC for which there is no targeted therapy. Chemotherapies remain the mainstay of treatment for TNBC, but their clinical efficacy is often limited by resistance. Immunotherapy is emerging as an exciting new treatment option for TNBC patients. While TNBC is more likely to respond to immunotherapy, overall response rate is still low. Developing novel and more effective TNBC therapies is an unmet biomedical need as most of advanced TNBCs do not respond well to current therapies. Epigenetic alterations such as DNA hypermethylation and histone dysregulation have been associated with all stages of TNBC formation and progression. Lysine-specific demethylase 1 (LSD1) is the first identified histone demethylase which specifically demethylates H3K4me1/2. LSD1 is a key component of multiple transcription repressor complexes. Tumors in TNBC patients frequently express higher level of LSD1 compared to other BC groups. Clinically, LSD1 protein overexpression is significantly associated with worse prognosis in TNBC patients, making it an attractive therapeutic target. Our recent study has revealed a new mechanism driving LSD1 protein overexpression in TNBC through HDAC5-mediated posttranslational modification. Treatment with LSD1 inhibitors effectively suppresses tumor progression and sensitizes TNBC cells to chemotherapeutic agents. Furthermore, LSD1 ablation stimulates antitumor immunity and potentiates the efficacy of anti-PD-1 antibody in poorly immunogenic TNBC. LSD1 inhibition leads to reexpression of a key epigenetically silenced tumor suppressor gene, Tissue Factor Pathway Inhibitor 2 (TFPI2), which is required for tumor suppression and responsiveness to immunotherapy. Based on these findings, we hypothesize that LSD1 overexpression facilitates TNBC development and inhibition of LSD1 improves TNBC therapies by inducing TFPI2-mediated cell killing and antitumor immunity.
Aim1. Determine the functional roles of LSD1 overexpression in TNBC development;
Aim2. Evaluate the in vitro and in vivo therapeutic efficacy of LSD1 inhibition against TNBC;
Aim3. Elucidate the immunogenic effects of LSD1 inhibition in TNBC. The results from the proposed studies are expected to provide new mechanistic insights and key preclinical evidence for using LSD1 inhibitors in TNBC. In the long run, these studies may lead to new and improved therapies for patients with relapsed and refractory TNBC.
This application proposes to identify a novel regulatory mechanism by which overexpression of oncoprotein LSD1 facilitates triple negative breast cancer (TNBC) progression. This project is also aimed at utilizing novel LSD1-targeting agents to enhance tumor suppression, augment antitumor immunity, and overcome therapeutic resistance in TNBC. The results from the proposed studies are expected to provide novel mechanistic insight and rationale for effective combination of leading LSD1 inhibitors with standard or immune therapies as new treatment strategies for patients with advanced TNBC.