Abstract
Simple SummaryAcquired resistance to antiestrogenic therapy remains the major obstacle to curing luminal subtype breast cancer. While current treatment in acquired endocrine-resistant settings includes combined therapy with receptor tyrosine kinase or cyclin-dependent kinase inhibitors, progression to incurable disease remains possible. In recent years, the antioxidant system and the protein quality control network have been associated with the enhanced resistance of breast cancer cells to hormonal therapy. In this work, we raise the hypothesis that antiestrogen treatment induces the accumulation of protein aggregates in sensitive cells, which in turn could hinder the activation of survival pathways. We present evidence concerning a novel way to identify antiestrogen response and disclose a novel protein, RTBC, that controls acquired antiestrogen resistance. This work opens a new avenue for research towards finding breast cancer prognostic markers and therapeutic targets, where the identification of proteins prone to aggregate could help to identify antiestrogen response and understand mechanisms of disease.The protein quality control network, including autophagy, the proteasome and the unfolded protein response (UPR), is triggered by stress and is overactive in acquired antiestrogen therapy resistance. We show for the first time that the aggresome load correlates with apoptosis and is increased in antiestrogen-sensitive cells compared to endocrine-resistant variants. LC-MS/MS analysis of the aggregated proteins obtained after 4OH-tamoxifen and Fulvestrant treatment identified proteins with essential function in protein quality control in antiestrogen-sensitive cells, but not in resistant variants. These include the UPR modulators RTCB and PDIA6, as well as many proteasome proteins such as PSMC2 and PSMD11. RTCB is a tRNA and XBP1 ligase and its aggregation induced by antiestrogens correlated with impaired XBP1s expression in sensitive cells. Knock down of RTCB was sufficient to restore sensitivity to tamoxifen in endocrine-resistant cells and increased the formation of aggresomes, leading to apoptotic cell death. Analysis of primary human breast cancer samples and their metastases appearing after endocrine treatment showed that RTCB is only localized to aggresomes in the primary tumors, while total aggresomes, including aggregated RTCB, were significantly reduced in the metastases. Therefore, different protein aggregation patterns may indicate loss of function of essential proteins resulting in enhanced protein aggregation that can be used to identify antiestrogen-resistant breast cancer cells and improve the response to antiestrogenic therapy.
Highlights
Development of resistance to endocrine therapy remains the main obstacle for curing estrogen receptor alpha (ERα)-positive breast cancer, with 30–50% of the patients that initially respond progressing to incurable disease [1,2]
Initiation of the IRE1α branch consists of an unconventional cytoplasmic splicing [17], where the IRE1α endoribonuclease domain removes an intron from the XBP1 mRNA followed by exon ligation by RNA-splicing ligase RtcB homolog (RTCB)
We show for the first time, that protein aggregation patterns differ between antiestrogensensitive and -resistant breast cancer cells, with aggregates containing essential proteasome and unfolded protein response (UPR) proteins found exclusively in endocrine-sensitive cells
Summary
Development of resistance to endocrine therapy remains the main obstacle for curing estrogen receptor alpha (ERα)-positive breast cancer, with 30–50% of the patients that initially respond progressing to incurable disease [1,2]. Pre-clinical studies have shown that the unfolded protein response (UPR) and autophagy (AUT) are enhanced, allowing breast cancer resistance to antiestrogen therapy [3,4,5,6,7,8,9]. Upon BIP releasing itself from the EnR-resident proteins (IRE1α, PERK and ATF6) to bind the misfolded proteins, the EnR-resident proteins initiate the three UPR cascades to restore proteostasis by inhibiting translation and increasing chaperoning and EnR capacity [15]. Inhibition of IRE1α activity or autophagy can reduce endocrine resistance in breast cancer [6,21,22], supporting the notion that unresolved protein aggregation could enhance drug toxicity
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