Targeting succinate dehydrogenase impairs the proliferation of ER+ breast cancer cells

Endocrine therapies (ET) for estrogen receptor positive (ER+) breast cancer directly block either estrogen biosynthesis (aromatase inhibitors) or estrogen receptor function (Fulvestrant or tamoxifen). However, due to intrinsic and acquired resistance, disease progression often resumes despite continued ET. Succinate dehydrogenase (SDH) enzyme catalyzes the reversible conversion of succinate to fumarate. It contains four different subunits and SDH assembly factor 2 (SDHAF2). In our study, we found elevated SDH enzymatic activity and protein expression of SDHB (catalytic subunit) in LCC9 (ET-resistant cells) comparison with LCC1 or MCF-7 (ET-sensitive cells). T47D-4HT (ET-resistant) also showed significantly higher protein levels of SDHB in comparison with their parental T47D-A18 cells (ET). Pharmacological inhibition of SDH activity using dimethylmalonate (DMM) reduced cell growth, colony and spheroid formation in both LCC9 and T47D-4HT. DMM treatment induced caspase-dependent apoptosis and reduced mitochondrial membrane potential in both LCC9 and T47D-4HT cells. Importantly, succinate accumulation was accompanied by HIF 1-alpha stabilization and SDH inhibition led to lower levels of HIF1-alpha, which indicates that SDH may function in the conversion of fumarate to succinate in LCC9 cells. Genetic ablation of SDHB confirmed the importance of SDH activity in growth, colony and spheroid formation of LCC9 and T47D-4HT cells. Taken together, SDH enzymatic activity is crucial for the proliferation and mitochondrial function of ET-resistant ER+ breast cancer cells. We propose that SDH is a potentially novel therapeutic target for ER+, endocrine therapy resistant breast cancer.