Mitochondrial estrogen receptors alter mitochondrial priming and response to endocrine therapy in breast cancer cells

Abstract

Breast cancer is the most common cancer with a high rate of mortality and morbidity among women worldwide. Estrogen receptor status is an important prognostic factor and endocrine therapy is the choice of first-line treatment in ER-positive breast cancer. However, most tumors develop resistance to endocrine therapy. Here we demonstrate that BH3 profiling technology, in particular, dynamic BH3 profiling can predict the response to endocrine therapy agents as well as the development of acquired resistance in breast cancer cells independent of estrogen receptor status. Immunofluorescence analysis and subcellular fractionation experiments revealed distinct ER-α and ER-β subcellular localization patterns in breast cancer cells, including mitochondrial localization of both receptor subtypes. shRNA-mediated depletion of ER-β in breast cancer cells led to resistance to endocrine therapy agents and selective reconstitution of ER-β in mitochondria restored sensitivity. Notably, mitochondria-targeted ER-α did not restore sensitivity, even conferred further resistance to endocrine therapy agents. In addition, expressing mitochondria-targeted ER-β in breast cancer cells resulted in decreased mitochondrial respiration alongside increased total ROS and mitochondrial superoxide production. Furthermore, our data demonstrated that mitochondrial ER-β can be successfully targeted by the selective ER-β agonist Erteberel. Thus, our findings provide novel findings on mitochondrial estrogen signaling in breast cancer cells and suggest the implementation of the dynamic BH3 technique as a tool to predict acquired endocrine therapy resistance.

Activators of the Anticipatory Unfolded Protein Response with Enhanced Selectivity for Estrogen Receptor Positive Breast Cancer

“…ErSO-DFP has potent activity, similar to ErSO , against other ERα+ breast cancer cell lines, including the T47D cell line and its therapy-resistant, ERα mutant versions, T47D-ERαY537S (TYS) and T47D-ERαD538G (TDG) (Table ). The cytostatic nature of selective estrogen receptor degraders/downregulators (SERDs) and selective estrogen receptor modulators (SERMs) and their activity dependence on estrogen levels are well established. , In our standard IC 50 assay, we use full fetal bovine serum (FBS) that contains unmeasured, high levels of estrogens with batch-to-batch variability, and ErSO and ErSO-DFP are potent and cytotoxic (indicated by high E max at 24 h) under these conditions, regardless of the estrogen level (Figure S2). This result contrasts cytostatic SERMs and SERDs (e.g., 4-hydroxytamoxifen and fulvestrant) that are not active at 24 h regardless of estrogen levels (Figure S2), consistent with the literature reporting a time course of cell death induced by SERM/SERDs …”

“…This result contrasts cytostatic SERMs and SERDs (e.g., 4hydroxytamoxifen and fulvestrant) that are not active at 24 h regardless of estrogen levels (Figure S2), consistent with the literature reporting a time course of cell death induced by SERM/SERDs. 28 Table 2. Parameters and Cellular Potencies for Ring B Derivatives a cLogD 7.4 was calculated using ChemAxon MarvinSketch (https:// chemaxon.com).…”

Silver nanoparticle-induced alteration of mitochondrial and ER homeostasis affects human breast cancer cell fate

“…Miscommunication between these organelles can lead to cellular bio-chemical dis-equilibrium shifting balance towards disorders [31] . Herein, a few studies show that induction of ER stress by NPs can impair cancer cell progression [31] , [34] , [35] , [36] . For example, AgNPs synthesized by Simard et al mediated ER stress and subsequent apoptosis in breast cancer cells [37] ; similarly, other research groups have also targeted both ER and mitochondrial activity by nano-formulations [38] , [39] ; however, the crosstalk between these two critical organelles in response to AgNP exposure is poorly understood.…”

Evolution of 3-(4-hydroxyphenyl)indoline-2-one as a scaffold for potent and selective anticancer activity

“…2B), BHPI, and other 3-(4-hydroxyphenyl)indoline-2-ones. 111,115 ErSO, like other chiral 3-(4-hydroxyphenyl)indoline-2-ones (as mentioned above), 109 has single enantiomer activity, with its opposite enantiomer lacking anticancer activity ((S)-1, Fig. 2B).…”