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

Alaknanda Adwal,Lucinda D Taege,Malcolm Lim,Priyakshi Kalita-De Croft,Sunil R Lakhani,Reshma Shakya,Emarene Kalaw,David F Callen,Jodi M Saunus,Amy E Mccart Reed

doi:10.26508/lsa.201900562

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 (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.

Highlights

The ubiquitin-proteasome system (UPS) is vital for cellular homeostasis, acting to regulate protein expression and eradicate oxidized, misfolded proteins
The relationship to Proteasome inhibitors (PIs) sensitivity was most noticeable for PSMB8, which was evident at the protein level (Fig 1D)
This was not a consequence of preferential i-proteasome inhibition, as the total proteasome activity was suppressed in both MDA-MB-468 (i-prothigh, low bortezomib LD50); and MCF-7 (i-protlow, low bortezomib LD50) (Fig 1E and F)

Summary

Introduction

The ubiquitin-proteasome system (UPS) is vital for cellular homeostasis, acting to regulate protein expression and eradicate oxidized, misfolded proteins. Basal-like breast cancer cell lines are dependent on i-proteasome activity i-relative to constitutive subunit in basal-A and claudin-low (basal-B) lines than luminal and HER2+ cell lines (Fig 1A and B). PSMB8-high, i-proteasome– addicted BC cell lines exhibit UPR-driven apoptosis in response to proteasome inhibition (Fig 2D).

Results

Conclusion