Abstract P3-05-07: The response of histone deacetylase inhibitors in triple negative breast cancer
Authors: Madlin Alzoubi, Khoa Nguyen, Hope Burks, Katherine Hebert, Thomas Cheng, Margarite Matossian, Maryl Wright, Bridgette Collins-Burow, Matthew Burow
Journal: Cancer Research (2022)

Abstract Breast cancer (BC) is the most prevalent type of cancer among women with triple negative breast cancer (TNBC) accounting for 15% of BC. The majority of BCs are hormone sensitive, TNBC, a more aggressive subtype is characterized by its negative expression of ER and PR, and lack of Her2/NEU amplification. Due to its receptor status, TNBC lacks targeted therapy. FK228 (Romidepsin), a class I and II histone deacetylase inhibitor (HDACi) has been approved by the FDA for the treatment of PTCL (peripheral T-cell lymphoma) and is a promising drug for TNBC treatment. FK228 mechanism of action was through cell cycle arrest and apoptosis (1,2). FK228 specifically targets the enzymes HDACs 1 and 2, tumor suppressor and other proteins thereby exerting epigenetic changes on cancer cells resulting in anti-tumor activity. To assess the role of HDACi, TNBC cell lines were treated with FK228 and Panobinostat (LBH, a panHDACi) and analyzed for suppression of cell cycle genes. Similar to PTCL, TNBC cell lines showed an increase in cell cycle arrest genes such as p21 and others subsequent to treatment with both drugs. Using PCR and crystal violet we identified changes in morphology and migration in 2k1, MDA-MB 231 and HS-578t cell lines treated with FK228 under in-vitro conditions. Further studies show a reversal of the epithelial to mesenchymal transition (EMT) in FK228 treated cells; specifically in key EMT genes CDH1 and ZEB2, both directly linked to HDAC1/2 activity. Similar results were replicated in 3D culture mammospheres. We are also further studying the effects of HDACi in vivo using PDXs (patient derived xenografts) in mouse models; the PDX is either injected as cells or implanted directly in the mammary pad. The PDX model is an excellent translational tool used to monitor growth patterns and recurrence, study metastasis and drug response. Thus far, the TU-BcX-2O0 PDX in vivo model demonstrated growth suppression in tumor growth with FK228 treatment. We are also studying FK228 in models TU-BX-4IC, 4M4 and 4QX. Metastasis in the models is monitored by H&amp;E staining lung and liver tissue for further staining and analysis; we are also using IVIS imaging in an in vivo model consisting of GFP/luciferase transfected breast cancer cells MDA-MB-231 and SUM-159 to monitor both the proliferation and spread of disease in mice. Ultimately we aim to characterize the pathways altered by FK228 and the involvement of HDACs in tumorigenesis, metastasis and resistance within TNBC. References: 1.Gisselbrecht, Christian, and David Sibon. “New Perspectives in the Therapeutic Approach of Peripheral T-Cell Lymphoma.” Current Opinion in Oncology, vol. 30, no. 5, 2018, pp. 285-291., doi:10.1097/cco.0000000000000469.2.Yang, L. P. (2011). Romidepsin. Drugs, 71(11), 1469-1480. doi:10.2165/11207170-000000000-00000 Citation Format: Madlin Alzoubi, Khoa Nguyen, Hope Burks, Katherine Hebert, Thomas Cheng, Margarite Matossian, Maryl Wright, Bridgette Collins-Burow, Matthew Burow. The response of histone deacetylase inhibitors in triple negative breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-05-07.