Abstract P5-08-02: Identify key regulators to modulate chemo-sensitivity of triple negative breast cancer by integrative analysis

Abstract

Abstract Triple negative breast cancer (TNBC), which is characterized by lack of expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor type 2 (HER2), is frequently associated with aggressive behavior and adverse patient outcomes and comprises a heterogeneous subgroup of tumors of diverse genomic features. Currently, TNBC patients are managed with only a few approved therapies and treatment strategies, including taxane-anthracycline chemotherapy. However, there is a subgroup of women with TNBC whose tumors are extremely sensitive to chemotherapy, but there are many women for whom chemotherapy is of uncertain benefit (1). To identify candidate therapeutic treatments for chemo-resistant patients of TNBC, we combined TNBC causal network modeling and chemo-response associated genes. We detected the differentially expressed genes according to chemo-responses by investigating expression profiles of TNBC samples with annotated information about responses to neoadjuvant chemotherapy(2), and constructed TNBC causal molecular network modeling by integrating epigenetic data with genetic, genomic, and transcriptomic data available for the Cancer Genome Atlas (TCGA) data(3). We leveraged the global causal network with genes associated with chemo-responses and detected highly connected chemo-sensitive subnetwork, which are enriched for Extracellular Matrix related pathways. The chemo-sensitive subnetwork was used to identify potential treatments to enhance chemosensitivity in two ways: 1) to identify key drivers that perturb genes within subnetwork based on number of directed connections, and 2) to identify repurposed therapeutics by comparing our chemo-sensitive subnetwork to the transcriptomic response to drug treatment(4). We identified the activity of microRNA let-7g was the most upstream key regulator that perturbs several collagen genes, suggesting the potential mechanism of chemosensitivity involved the extracellular matrix pathway. Additionally, we predicted candidate drugs including Genistein to modulate chemo-sensitivity, which was experimentally validated in TNBC cell lines. Taken together, the results demonstrated that our novel integrative approach of multi-omics data is useful to identify potential therapeutic targets to treat chemo-resistant TNBC patients by modulating chemo-sensitivity. 1. Bianchini, G., Balko, J.M., Mayer, I.A., Sanders, M.E. and Gianni, L. (2016) Triple-negative breast cancer: challenges and opportunities of a heterogeneous disease. Nature reviews. Clinical oncology. 2. Hatzis, C., Pusztai, L., Valero, V., Booser, D.J., Esserman, L., Lluch, A., Vidaurre, T., Holmes, F., Souchon, E., Wang, H. et al. (2011) A genomic predictor of response and survival following taxane-anthracycline chemotherapy for invasive breast cancer. Jama, 305, 1873-1881. 3. Cancer Genome Atlas, N. (2012) Comprehensive molecular portraits of human breast tumours. Nature, 490, 61-70. 4. Lamb, J., Crawford, E.D., Peck, D., Modell, J.W., Blat, I.C., Wrobel, M.J., Lerner, J., Brunet, J.P., Subramanian, A., Ross, K.N. et al. (2006) The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease. Science, 313, 1929-1935. Citation Format: Lee E, Ito K, Irie HY, Zhu J. Identify key regulators to modulate chemo-sensitivity of triple negative breast cancer by integrative analysis [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-08-02.