Treatment of advanced breast cancer remains challenging. Copper and some of the copper-dependent proteins are emerging therapeutic targets because they are essential for cell proliferation and survival, and have been shown to stimulate angiogenesis and metastasis. Here, we show that DCAC50, a recently developed small-molecule inhibitor of the intracellular copper chaperones, ATOX1 and CCS, reduces cell proliferation and elevates oxidative stress, triggering apoptosis in a panel of triple-negative breast cancer (TNBC) cells. Inhibition of ATOX1 activity with DCAC50 disrupts copper homeostasis, leading to increased copper levels, altered spatial copper redistribution, and accumula-tion of ATP7B to the cellular perinuclear region. The extent and impact of this disruption to copper homeostasis vary across cell lines and correlate with cellular baseline copper and glutathione levels. Ultimately, treatment with DCAC50 attenuates tumor growth and suppresses angiogenesis in a xenograft mouse model, and prevents endothelial cell network formation in vitro. Co-treatment with paclitaxel and DCAC50 enhances cytotoxicity in TNBC and results in favorable dose reduction of both drugs. These data demonstrate that inhibition of intracellular copper transport targets tumor cells and the tumor microenvironment, and is a promising approach to treat breast cancer.
Bi-annual MRI performed well for early detection of invasive breast cancer in genomically stratified high-risk women. No benefit was associated with annual MG screening plus bi-annual MRI screening.
Word frequency is an important predictor of lexical-decision task performance. The current study further examined the role of this variable by exploring the influence of frequency trajectory. Frequency trajectory is measured by how often a word occurs in childhood relative to adulthood. Past research on the role of this variable in word recognition has produced equivocal results. In the current study, words were selected based on their frequencies in Grade 1 (child frequency) and Grade 13 (college frequency). In Experiment 1, four frequency trajectory conditions were factorially examined in a lexical-decision task with English words: high-to-high (world), high-to-low (uncle), low-to-high (brain) and low-to-low (opera). an interaction between Grade 1 and college frequency demonstrated that words in the low-to-high condition were processed significantly faster and more accurately than words in the low-to-low condition, whereas the high-to-high and high-to-low conditions did not differ significantly. In Experiment 2, an advantage for words with an increasing frequency trajectory was also supported in regression analyses on both lexical decision and naming times for 3,039 items selected from the English Lexicon Project (Balota et al., 2007). This was replicated in Experiment 3, based on a regression analysis of 2,680 words from the British Lexicon Project (BLP; Keuleers, Lacey, Rastle, & Brysbaert, 2012). In all analyses, rated age-of-acquisition also significantly impacted word recognition. Together, the results suggest that the age at which a word is initially learned as well as its frequency trajectory across childhood impact performance in the lexical-decision task. (PsycINFO Database Record
<p>Figure S1 - Western blot images showing ATOX1 and CCS levels in TNBC cells, corresponding to data presented in Figure 1. Figure S2 - Dose-response profiles of TM in TNBC cells and DCAC50 in HMEC; caspase-3/7 activity after DCAC50 treatment of HMEC. Figure S3 - Copper content, copper distribution and iron and zinc content for DCAC50-treated TNBC cells, supplementing Figure 3. Figure S4 - Protein levels of copper transporters, GSH levels, GSH depletion experiments and SOD1 activity levels in TNBC cells in response to DCAC50 treatment, supplementing Figure 4. Figure S5 - Dose-response profile for DCAC50 and caspase-3/7 activity after DCAC50 treatment in HuVEC. Figure S6 - Evaluation of DCAC50 treatment on tumor volumes and angiogenesis in MDA-MB-468 and MDA-MB-231 xenograft mouse models, supplementing Figure 5. Supplementary Methods ¬- Information about the antibodies and detailed procedures used for Western blot, immunofluorescent staining and SOD activity assay.</p>
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