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Article

Protein Aggregation Patterns Inform about Breast Cancer Response to Antiestrogens and Reveal the RNA Ligase RTCB as Mediator of Acquired Tamoxifen Resistance

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iBiMED—Institute of Biomedicine, University of Aveiro, 3810-193 Aveiro, Portugal
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LaQV-REQUIMTE—Associated Laboratory for Green Chemistry of the Network of Chemistry and Technology, University of Aveiro, 3810-193 Aveiro, Portugal
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Department of Pathology, Portuguese Oncology Institute of Porto (IPOP), 4200-072 Porto, Portugal
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Cancer Biology and Epigenetics Group, IPO Porto Research Center (GEBC CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto) & Porto Comprehensive Cancer Center (P.CCC), 4200-072 Porto, Portugal
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Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar, University of Porto (ICBAS-UP), Rua Jorge Viterbo Ferreira 228, 4050-513 Porto, Portugal
*
Author to whom correspondence should be addressed.
Academic Editor: Susan Logue
Cancers 2021, 13(13), 3195; https://doi.org/10.3390/cancers13133195
Received: 13 May 2021 / Revised: 8 June 2021 / Accepted: 18 June 2021 / Published: 26 June 2021
(This article belongs to the Special Issue Novel Biomarkers and Molecular Targets in Cancer)
Acquired 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. View Full-Text
Keywords: breast cancer; estrogen receptors; antiestrogen resistance; protein aggregation; tRNA-splicing ligase RTCB homolog (RTCB) breast cancer; estrogen receptors; antiestrogen resistance; protein aggregation; tRNA-splicing ligase RTCB homolog (RTCB)
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MDPI and ACS Style

Direito, I.; Monteiro, L.; Melo, T.; Figueira, D.; Lobo, J.; Enes, V.; Moura, G.; Henrique, R.; Santos, M.A.S.; Jerónimo, C.; Amado, F.; Fardilha, M.; Helguero, L.A. Protein Aggregation Patterns Inform about Breast Cancer Response to Antiestrogens and Reveal the RNA Ligase RTCB as Mediator of Acquired Tamoxifen Resistance. Cancers 2021, 13, 3195. https://doi.org/10.3390/cancers13133195

AMA Style

Direito I, Monteiro L, Melo T, Figueira D, Lobo J, Enes V, Moura G, Henrique R, Santos MAS, Jerónimo C, Amado F, Fardilha M, Helguero LA. Protein Aggregation Patterns Inform about Breast Cancer Response to Antiestrogens and Reveal the RNA Ligase RTCB as Mediator of Acquired Tamoxifen Resistance. Cancers. 2021; 13(13):3195. https://doi.org/10.3390/cancers13133195

Chicago/Turabian Style

Direito, Inês, Liliana Monteiro, Tânia Melo, Daniela Figueira, João Lobo, Vera Enes, Gabriela Moura, Rui Henrique, Manuel A.S. Santos, Carmen Jerónimo, Francisco Amado, Margarida Fardilha, and Luisa A. Helguero 2021. "Protein Aggregation Patterns Inform about Breast Cancer Response to Antiestrogens and Reveal the RNA Ligase RTCB as Mediator of Acquired Tamoxifen Resistance" Cancers 13, no. 13: 3195. https://doi.org/10.3390/cancers13133195

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