Abstract P4-10-27: Epigenetic Drug Profiling for Breast Cancer Therapy: A Focus on Receptor Modulation and Heterogeneity

Abstract Breast cancer is the second leading cause of cancer death in women. The primary cause of mortality is associated with the metastasis process of cancer cells to other organs. It has become obvious that epigenetic alteration plays a crucial role in breast cancer progression through the modulation of various signaling pathways. Additionally, the plastic nature of cancer cells is essential to their adaption in different metastatic sites. However, implementing epigenetic therapies in the clinic has been challenging due to the ubiquitous expression of many epigenetic factors. Here, we evaluate a library of epigenetic drugs to determine their impact on receptors commonly targeted in breast cancer. These include estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). We coupled an immuno-fluorescence imaging approach to bioluminescence imaging to capture receptor heterogeneity and the proliferation index of each epigenetic drug. So far, we have assessed 460 drugs that target various factors, including Epigenetics, JAK/STAT, DNA Damage, Angiogenesis, Cell Cycle, PI3K/Akt/mTOR and Cytoskeletal Signaling targeting and histone deacetylases (HDACs), DNA methyltransferases (DNMTs), histone methyltransferases (HMTs), aurora kinase PARP, Sirtiin, EGFR, JAK, Plm pathways. We also analyzed the expression of key epigenetic markers (e.g., EZH2) and stemness-associated factors (e.g., SOX9). As a result, we found BIO, an inhibitor of GSK-3 and JAK, increases ER expression. Similarly, Curcumin, an inhibitor of p300 histone acetyl-transferase and Histone deacetylase (HDAC) promotes a broader range of factors, including Her2, Sox9, and ER. Interestingly, (+)-JQ1(BET bromodomain inhibitor), I-BRD9 (BRD9 inhibitor) and CUDC-101 (HDAC inhibitor) drastically reduced Ki67 level. Overall, these findings suggest a potential for combination therapy. While further investigation of these promising candidates is needed (3D, ex vivo, and in vivo testing), this investigation reveals new possibilities to overcome therapeutic resistance in breast cancer. Citation Format: Rahat Alam, Igor Bado. Epigenetic Drug Profiling for Breast Cancer Therapy: A Focus on Receptor Modulation and Heterogeneity [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P4-10-27.