Carfilzomib公司
三阴性乳腺癌
蛋白酶体
癌症研究
硼替佐米
乳腺癌
免疫系统
生物
蛋白酶体抑制剂
佐剂
免疫学
癌症
医学
内科学
多发性骨髓瘤
细胞生物学
作者
Alaknanda Adwal,Priyakshi Kalita‐de Croft,Reshma Shakya,Malcolm Lim,Emarene Kalaw,Lucinda Taege,Amy E. McCart Reed,Sunil R. Lakhani,David F. Callen,Jodi M. Saunus
出处
期刊:Life science alliance
[Life Science Alliance]
日期:2020-05-18
卷期号:3 (7): e201900562-e201900562
被引量:16
标识
DOI:10.26508/lsa.201900562
摘要
In vitro studies have suggested proteasome inhibitors could be effective in triple-negative breast cancer (TNBC). We found that bortezomib and carfilzomib induce proteotoxic stress and apoptosis via the unfolded protein response (UPR) in TNBC cell lines, with sensitivity correlated with expression of immuno-( PSMB8/9/10 ) but not constitutive-( PSMB5/6/7 ) proteasome subunits. Equally, the transcriptomes of i-proteasome–high human TNBCs are enriched with UPR gene sets, and the genomic copy number landscape reflects positive selection pressure favoring i-proteasome activity, but in the setting of adjuvant treatment, this is actually associated with favorable prognosis. Tumor expression of PSMB8 protein (β5i) is associated with levels of MHC-I, interferon-γ–inducible proteasome activator PA28β, and the densities of stromal antigen-presenting cells and lymphocytes (TILs). Crucially, TILs were protective among TNBCs that maintain high β5i but did not stratify survival amongst β5i-low TNBCs. Moreover, β5i expression was lower in brain metastases than in patient-matched primary breast tumors (n = 34; P = 0.007), suggesting that suppression contributes to immune evasion and metastatic progression. Hence, inhibiting proteasome activity could be counterproductive in the adjuvant treatment setting because it potentiates anti-TNBC immunity.
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