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Tradeoff between metabolic i-proteasome addiction and immune evasion in triple-negative breast cancer.

ABSTRACT: 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 (?5i) is associated with levels of MHC-I, interferon-?-inducible proteasome activator PA28?, and the densities of stromal antigen-presenting cells and lymphocytes (TILs). Crucially, TILs were protective among TNBCs that maintain high ?5i but did not stratify survival amongst ?5i-low TNBCs. Moreover, ?5i 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.

SUBMITTER: Adwal A

PROVIDER: S-EPMC7240743 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Tradeoff between metabolic i-proteasome addiction and immune evasion in triple-negative breast cancer.

Adwal Alaknanda A Kalita-de Croft Priyakshi P Shakya Reshma R Lim Malcolm M Kalaw Emarene E Taege Lucinda D LD McCart Reed Amy E AE Lakhani Sunil R SR Callen David F DF Saunus Jodi M JM

Life science alliance 20200518 7

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-(<i>PSMB8/9/10</i>) but not constitutive-(<i>PSMB5/6/7</i>) proteasome subunits. Equally, the transcriptomes of i-proteasome-high human TNBCs are enriched with UPR gene sets, and the genomic ...[more]

PMID: 32423906

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Project description:BackgroundAlthough immune checkpoint blockade has emerged as a novel promising strategy for triple-negative breast cancer (TNBC), many patients fail response or acquire resistance to current agents. Consequently, our focus need to shift toward alternative inhibitory targets, predictor for responsiveness, and immune suppressive mechanisms.MethodsIn this study, we performed systematic bioinformatics analyses to identify PPP2R2B as a robust tumor suppressor in TNBC. Meanwhile, breast cancer progression cell line model was applied in our research. Quantitative real-time PCR assay (Q-PCR) was carried out to assess the role of PPP2R2B in the onset and progression of breast cancer. Furthermore, we validated the effect of PPP2R2B on immune activity via in vitro experiments based on macrophages. To further decipher the roles of PPP2R2B in TNBC, we investigated the transcriptome level, genomic profiles, and its clinical prognostic value.ResultsIn TNBC tissues, PPP2R2B expression was significantly downregulated compared to normal breast tissues. Kaplan-Meier survival analysis revealed that patients with low PPP2R2B expression had shorter survival time than those with high PPP2R2B expression. Q-PCR analysis suggested that PPP2R2B downregulation could play a key role in breast-cancer initiation and progression. Additionally, our findings showed that PPP2R2B was positively related with CD8 T cells, CD4 Th1 helper cells, and M1 macrophages, but negatively related with M2 macrophages. Subsequent results identified that PPP2R2B was strongly related with immune inhibitor genes (GZMA, PRF1, and IFNG), which could improve T lymphocytes antitumor function and restrict immune evasion. Meanwhile, T cell receptor signaling pathway and antigen processing and presentation signaling pathway were significantly suppressed in low PPP2R2B expression group. Afterwards, distinct subgroups based on PPP2R2B expression exhibited several unique features in somatic mutations, copy numbers alterations, extent of copy number burden, and promoter methylation level.ConclusionOur results indicated that PPP2R2B could serve as a promising biomarker for TNBC, and help predict immunotherapeutic response and guide personalized strategies in TNBC treatment.

Dataset Information

Tradeoff between metabolic i-proteasome addiction and immune evasion in triple-negative breast cancer.

Publications

Tradeoff between metabolic i-proteasome addiction and immune evasion in triple-negative breast cancer.

Similar Datasets

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