Inhibition of USP2 Induces Apoptosis through Down Regulation of Fatty Acid Synthase and Cyclin D1 in Triple Negative Breast Cancer

Abstract

Background: Breast cancer is the most occurring cancer in women with high incidence rates both in developed and developing countries. Among different types of breast cancers, Triple Negative Breast Cancer (TNBC) is the most aggressive type as it lacks receptors of Estrogen, Progesterone and Human Epidermal Growth Factor Receptor 2, common diagnostic biomarkers for the disease. Since early detection of TNBC can save thousands of lives, there is a dire need to discover and develop effective and affordable methods for early detection. Different Post Translational Modifications (PTMs) have been proposed as potential biomarker for various clinical conditions. Ubiquitination is a type of PTM involved in the stability and regulation of cellular proteins. Objective: It is hypothesized that reticence of ubiquitination may lead to cell death. Current study focuses on the inhibition of Ubiquitin Specific Protease (USP), USP2 using its inhibitor, ML364 in HTB- 132 triple negative breast cancer cell line to induce cell death. The aim of the current study was to evaluate anticancer property of ML364 that might be a promising novel therapeutic agent for TNBC. Furthermore, current investigations focus on USP2 and their focal stabilizing substrates i.e. Fatty acid Synthase (FAS) and Cyclin D1 could be potential prognostic markers for the disease. Methods: Quantitative PCR of CyclinD1, USP2, MDM2, and Fatty Acid Synthase (FAS) was performed to identify the deubiquitination effect of ML364 in breast cancer cells, which complemented our results with studies on normal and breast cancerous tissue samples. Results: Expression of USP2 and its substrates Cyclin D1and FAS was found to be down regulated in ML364 treated breast cancer cell line whereas higher expression was observed in breast cancer tissue, indicating therapeutic potential of USP2 inhibitor. Conclusion: Our findings suggest that USP2, Cyclin D1 and FAS could be used as prognostic marker and therapeutic target for TNBC.