Protein Aggregation Patterns Inform about Breast Cancer Response to Antiestrogens

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Protein Aggregation Patterns Inform about Breast Cancer Response to Antiestrogens

Monday, 02.08.2021

Authors and Affiliations:

Inês Direito1, Liliana Monteiro1, Tânia Melo2, Daniela Figueira1, João Lobo3,4,5, Vera Enes1, Gabriela Moura1, Rui Henrique3,4,5, Manuel A. S. Santos1, Carmen Jerónimo3,4,5, Francisco Amado2, Margarida Fardilha1 e Luisa A. Helguero1

1 iBiMED—Institute of Biomedicine, Universidade de Aveiro, 3810-193 Aveiro, Portugal;

2 LaQV-REQUIMTE—Associated Laboratory for Green Chemistry of the Network of Chemistry and Technology, Universidade de Aveiro, 3810-193 Aveiro, Portugal;

3 Departamento de Patologia, Instituto Português de Oncologia do Porto (IPOP), 4200-072 Porto, Portugal;

4 Cancer Biology and Epigenetics Group, IPO Porto Research Center (GEBC CI-IPOP), Instituto Português de Oncologia do Porto (IPOP) & Porto Comprehensive Cancer Center (P.CCC), 4200-072 Porto,Portugal

5 Departamento de Patologia e Imunologia Molecular, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto (ICBAS-UP), Rua Jorge Viterbo Ferreira 228, 4050-513 Porto, Portugal



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.