The proteasome inhibitor Bortezomib (Velcade) as potential inhibitor of estrogen receptor-positive breast cancer

Abstract

Around 70% of breast cancers express the estrogen receptor a (ERa) and depend on estrogen for growth, survival and disease progression. The presence of hormone sensitivity is usually associated with a favorable prognosis. Use of adjuvant antiendocrine therapy has significantly decreased breast cancer mortality in patients with early-stage disease, and anti-endocrine therapy also plays a central role in the treatment of advanced stages. However a subset of hormone receptor-positive breast cancers do not benefit from anti-endocrine therapy, and nearly all hormone receptor-positive metastatic breast cancers ultimately develop resistance to anti-hormonal therapies. Despite new insights into mechanisms of anti-endocrine therapy resistance, e.g., crosstalk between ERa and Her2/neu, the management of advanced hormone-receptor-positive breast cancers that are resistant to anti-endocrine agents remains a significant challenge. In the present study, we demonstrate that the proteasome inhibitor Bortezomib strongly inhibits ERa and HER2/neu expression, increases expression of cyclin-dependent kinase inhibitors, inhibits expression of multiple genes associated with poor prognosis in ERa1 breast cancer patients and induces cell death in ER1 breast cancer cells in both the presence and absence of functional p53. Although Bortezomib increased the levels of p53 and increased the expression of pro-apoptotic target genes in ERa1 breast cancer cells harboring wild-type p53, Bortezomib also exerts anti-tumoral effects on ERa1 breast cancer cells through suppression of ERa expression and inhibition of PI3K/Akt/mammalian target of rapamycin (mTOR) and ERK signaling independently of functional p53. These findings suggest that Bortezomib might have the potential to improve the management of anti-endocrine therapy resistant ERa1 breast cancers independently of their p53 status.

Resveratrol fuels HER2 and ERα-positive breast cancer behaving as proteasome inhibitor

“…Our results also support the hypothesis that resveratrol may exert its anti-ERα action by impairing proteasome-mediated ERα activation. Interestingly, UPS has been described as necessary for a correct activation of ERα [40] and some proteasome inhibitors have been shown to repress ERα gene expression [41, 42]. Moreover, a recently published work has proposed that mTORC1 inhibition activates the Ubiquitin/Proteasome System (UPS) and autophagy [43], thus sustaining an inverse correlation between mTOR signaling and proteasome activity.…”

“…For the in vitro experiments resveratrol was dissolved in DMSO (Sigma) and then diluted in complete DMEM to usage concentrations (10-100 μM). 17β-estradiol (Calbiochem) was used as control estrogen treatment (stock solution 40 mM in 100% ethanol and diluted in complete DMEM to 10 nM), as previously described [41]. Cells were treated for 24 hours with resveratrol/17β-estradiol- or vehicle-containing medium (0.02% DMSO).…”

A functional drug re-purposing screening identifies carfilzomib as a drug preventing 17β-estradiol: ERα signaling and cell proliferation in breast cancer cells

“…Remarkably, the fact that E2 is still able to trigger ERα degradation in the presence of carfilzomib suggests that this drug does not bind to ERα and that its effects depend on the ability of the drug to inhibit the 26S proteasome. Accordingly, treatment of BC cell lines with other inhibitors of 26S proteasome activity (e.g., bortezomib -Velcade®) reduces ERα levels and consequently prevents receptor-dependent signaling [39]. The apparent paradox that 26S proteasome inhibitors reduce the levels of ERα, which turnover is, at least in part, controlled by the 26S proteasome itself can be reconciled by considering that the irreversible inhibition of 26S proteasome leads to a high accumulation of ubiquitinated species, which cells remove by activating autophagy [40,41].…”

Network integration of multi-tumour omics data suggests novel targeting strategies

“…to Bortezomib (proteasome activity inhibitor 35,36 ), with a significant synergic action at several dosages, suggesting a novel therapeutic strategy to be further explored in preclinical models of cluster 2 tumours. These observations indicate that our study succeeded in: 1) clustering tumours highlighting common functional mechanisms related to their transcriptional profile, and 2) selecting genes with a relevant functional role in the studied tumours, thus amenable of drug targeting.…”