Study of BiP and TARDBP clinical significance as immunohistochemical markers for breast cancer prognosis
Autor(a) principal: | |
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Data de Publicação: | 2022 |
Tipo de documento: | Dissertação |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10773/35649 |
Resumo: | Breast cancer (BC) is the most common cancer among women and one of the most common malignancies worldwide. BC is classified into subgroups to facilitate diagnosis, prognosis, and therapy options. Nearly 70% of breast tumours express the estrogen receptor (ER), offering hormone therapy as a viable treatment option. BC is a heterogeneous disease with many invasiveness-related variables, such as stage, grade, lymph node invasion, histology and hormone-receptor status. Resistance to antiestrogenic (AE) therapy remains the main problem of breast cancer treatment. In this work, the focus was on two proteins: TARDBP and BiP. TARDBP is a protein that plays important roles in transcription, pre-mRNA processing, splicing, and translation. This protein is well characterized in neurodegenerative disorders; however, little is known of its effects in BC. BiP is an endoplasmic reticulum (EndR) chaperone responsible for protein folding, calcium homeostasis and also acts as stress sensor. BiP is the primary regulator of EndR stress and exhibits antiapoptotic properties that regulate the unfolded protein response (UPR) signaling. BC therapies increase UPR signaling, hence promoting cell survival and drug resistance. The purpose of this research was to determine if BiP and TARDBP expression might be employed as predictive and prognostic indicators in luminal BC. The expression of TARDBP and BiP was analyzed in two small retrospective cohorts: cohort 1 with treatment naïve biopsies and its paired treated tumour sample; and cohort 2 with primary tumour samples and its corresponding metastasis. TARDBP expression was reduced in treated tumours relative to untreated biopsies, and this drop may be related with lower grade and increased progesterone receptor (PR) expression. BiP expression increased in metastasis compared to the primary tumour, which might be connected to the HER2 receptor. A knockdown of TARDBP was also performed, using siRNA, following treatment with tamoxifen. Regardless of treatment, cell proliferation decreased, demonstrating that this protein is essential for cell survival. To study BiP’s clinicopathological potential, complementary approaches were used: a systematic review and meta-analysis of immunohistochemistry (IHC) detection of BIP in human BC, as well as an examination of publicly accessible RNA-seq and proteomics datasets stratified by high and low quartile, were conducted. HER2, Basal-like subtypes, and greater immune score were related with elevated BiP mRNA and protein in the TCGA PanCancer dataset and CPTAC. BiP positivity was associated with worse relapse-free survival in BiP IHC meta-analysis. BiP IHC demonstrated elevated BiP expression in metastatic tumours, a correlation between BiP positivity and HER2 expression, and nuclear BiP localization as a predictor of advanced tumour stage and poor prognosis was observed. Thus, distinct methods demonstrated that BiP protein is associated with worse outcomes and may have a predictive value for BC. In conclusion, TARDBP expression is essential for cell survival and its decrease following AE therapy may be associated with less aggressive tumours. In contrast, complementary analyses of BiP reveal that BiP expression is higher in metastasis and in triple negative BC (TNBC), both associated with more aggressive tumors, suggesting that BiP is indicative of a poor prognosis. |
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Study of BiP and TARDBP clinical significance as immunohistochemical markers for breast cancer prognosisProtein aggregationChaperoneBreast cancerTumour heterogeneityBiPTARDBPUPRImmunohistochemistryAntiestrogen resistanceHormonal therapyMetanalysisBreast cancer (BC) is the most common cancer among women and one of the most common malignancies worldwide. BC is classified into subgroups to facilitate diagnosis, prognosis, and therapy options. Nearly 70% of breast tumours express the estrogen receptor (ER), offering hormone therapy as a viable treatment option. BC is a heterogeneous disease with many invasiveness-related variables, such as stage, grade, lymph node invasion, histology and hormone-receptor status. Resistance to antiestrogenic (AE) therapy remains the main problem of breast cancer treatment. In this work, the focus was on two proteins: TARDBP and BiP. TARDBP is a protein that plays important roles in transcription, pre-mRNA processing, splicing, and translation. This protein is well characterized in neurodegenerative disorders; however, little is known of its effects in BC. BiP is an endoplasmic reticulum (EndR) chaperone responsible for protein folding, calcium homeostasis and also acts as stress sensor. BiP is the primary regulator of EndR stress and exhibits antiapoptotic properties that regulate the unfolded protein response (UPR) signaling. BC therapies increase UPR signaling, hence promoting cell survival and drug resistance. The purpose of this research was to determine if BiP and TARDBP expression might be employed as predictive and prognostic indicators in luminal BC. The expression of TARDBP and BiP was analyzed in two small retrospective cohorts: cohort 1 with treatment naïve biopsies and its paired treated tumour sample; and cohort 2 with primary tumour samples and its corresponding metastasis. TARDBP expression was reduced in treated tumours relative to untreated biopsies, and this drop may be related with lower grade and increased progesterone receptor (PR) expression. BiP expression increased in metastasis compared to the primary tumour, which might be connected to the HER2 receptor. A knockdown of TARDBP was also performed, using siRNA, following treatment with tamoxifen. Regardless of treatment, cell proliferation decreased, demonstrating that this protein is essential for cell survival. To study BiP’s clinicopathological potential, complementary approaches were used: a systematic review and meta-analysis of immunohistochemistry (IHC) detection of BIP in human BC, as well as an examination of publicly accessible RNA-seq and proteomics datasets stratified by high and low quartile, were conducted. HER2, Basal-like subtypes, and greater immune score were related with elevated BiP mRNA and protein in the TCGA PanCancer dataset and CPTAC. BiP positivity was associated with worse relapse-free survival in BiP IHC meta-analysis. BiP IHC demonstrated elevated BiP expression in metastatic tumours, a correlation between BiP positivity and HER2 expression, and nuclear BiP localization as a predictor of advanced tumour stage and poor prognosis was observed. Thus, distinct methods demonstrated that BiP protein is associated with worse outcomes and may have a predictive value for BC. In conclusion, TARDBP expression is essential for cell survival and its decrease following AE therapy may be associated with less aggressive tumours. In contrast, complementary analyses of BiP reveal that BiP expression is higher in metastasis and in triple negative BC (TNBC), both associated with more aggressive tumors, suggesting that BiP is indicative of a poor prognosis.O cancro da mama (CM) o cancro mais comum entre mulheres e um dos mais comuns em todo o mundo. O CM é classificado em subgrupos para facilitar o diagnóstico, prognóstico e as opções de tratamento. Cerca de 70% dos tumores mamários expressam recetores de estrogénio (ER), sendo a terapia hormonal uma opção viável de tratamento. O CM é uma doença heterogénea dependente de várias variáveis, como o estadio, o grau, os nódulos linfáticos, a histologia e a expressão de recetores hormonais. A resistência à terapia com anti-estrogénios continua a ser o principal obstáculo ao tratamento do CM. Neste trabalho, foi dado foco a duas proteínas: TARDBP e BiP. TARDBP é uma proteína que desempenha funções importantes, tais como a transcrição, o processamento de pré-mRNA, o splicing e tradução. Esta proteína é bem caracterizada em doenças neurodegenerativas; no entanto, pouco se sabe sobre esta proteína no CM. BiP é uma chaperona do retículo endoplasmático (EndR) responsável pelo folding de proteínas, pela homeostase de cálcio e é também um sensor de stress. BiP é o principal regulador do stress do EndR e exibe propriedades antiapoptóticas que, por sua vez, regulam a resposta à perda de folding das proteínas (Unfolded Protein Response: UPR). As terapias do CM aumentam a sinalização da UPR, que por sua vez, promove a sobrevivência celular e a resistência a medicamentos. O objetivo deste trabalho é determinar se as proteínas TARDBPe BiP podem ser aplicadas como indicadores preditivos e de prognostico no CM luminais. A expressão de TARDBP e de BiP foi analizada em duas pequenas coortes retrospetivas: coorte 1 que consistia em amostras de biópsias sem tratamento e a sua respetiva amostra de tumor após tratamento; e a coorte 2 que consistia em tumores primários e as suas metástases correspondentes. A expressão de TARDBP reduziu nas amostras tratadas, em comparação com as biópsias, e essa queda pode estar relacionada com o baixo grau e com uma maior percentagem de recetores de progesterona (PR). A expressão de BiP aumentou nas metastases, em comparação com os tumoures primarios, o que pode estar relacionado com a expressão de recetores de HER2. Também foi realizado um knockdown de TARDBP, com siRNA, seguido de tramento de tamofixeno em células MCF-7.A proliferação celular diminui independentemente do tratamento. Para o estudo da proteína BiP, foram usadas análises complementares: uma revisão sistemática e meta-análise sobre a deteção de BiP por imunohistoquímica (IHC) no CM, assim como uma análise de bases de dados públicas sobre RNA-seq e proteómica, estratificada em quartil menor ou maior de acordo com os níveis de proteína. Os subtipos HER2 e basal-like, assim como um maior score immune foram relacionados com uma maior expressão de BiP mRNA e proteína, segundo a base de dados TCGA, PanCancer e CPTAC. A positividade de BiP foi relacionada com pior sobrevida livre de na meta-análise. A análise de IHC de BiP demonstrou uma elevada expressão nas metastases, uma correlação entre a positividade de BiP e a expressão de HER2 e a uma sublocalização nuclear como fatores preditivos nos tumores com estadio avançado e pior prognóstico. Deste modo, métodos distintos demonstratam que a proteína BiP está associada a piores outcomes e pode ter valor preditivo no BC. Em nota de conclusão, a proteína TARDBP é essencial para a sobrevivência celular e o decréscimo da sua expressão pode estar associado a tumores menos agressivos. Por outro lado, análises completares da proteína BiP revelaram que a sua expressão é mais elevada em metástases e em CM triplo, ambos relacionados com maior agressividade tumoral.2024-11-29T00:00:00Z2022-11-29T00:00:00Z2022-11-29info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisapplication/pdfhttp://hdl.handle.net/10773/35649engGomes, Daniela Filipa Costainfo:eu-repo/semantics/embargoedAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2024-02-22T12:08:43Zoai:ria.ua.pt:10773/35649Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-20T03:06:38.978320Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Study of BiP and TARDBP clinical significance as immunohistochemical markers for breast cancer prognosis |
title |
Study of BiP and TARDBP clinical significance as immunohistochemical markers for breast cancer prognosis |
spellingShingle |
Study of BiP and TARDBP clinical significance as immunohistochemical markers for breast cancer prognosis Gomes, Daniela Filipa Costa Protein aggregation Chaperone Breast cancer Tumour heterogeneity BiP TARDBP UPR Immunohistochemistry Antiestrogen resistance Hormonal therapy Metanalysis |
title_short |
Study of BiP and TARDBP clinical significance as immunohistochemical markers for breast cancer prognosis |
title_full |
Study of BiP and TARDBP clinical significance as immunohistochemical markers for breast cancer prognosis |
title_fullStr |
Study of BiP and TARDBP clinical significance as immunohistochemical markers for breast cancer prognosis |
title_full_unstemmed |
Study of BiP and TARDBP clinical significance as immunohistochemical markers for breast cancer prognosis |
title_sort |
Study of BiP and TARDBP clinical significance as immunohistochemical markers for breast cancer prognosis |
author |
Gomes, Daniela Filipa Costa |
author_facet |
Gomes, Daniela Filipa Costa |
author_role |
author |
dc.contributor.author.fl_str_mv |
Gomes, Daniela Filipa Costa |
dc.subject.por.fl_str_mv |
Protein aggregation Chaperone Breast cancer Tumour heterogeneity BiP TARDBP UPR Immunohistochemistry Antiestrogen resistance Hormonal therapy Metanalysis |
topic |
Protein aggregation Chaperone Breast cancer Tumour heterogeneity BiP TARDBP UPR Immunohistochemistry Antiestrogen resistance Hormonal therapy Metanalysis |
description |
Breast cancer (BC) is the most common cancer among women and one of the most common malignancies worldwide. BC is classified into subgroups to facilitate diagnosis, prognosis, and therapy options. Nearly 70% of breast tumours express the estrogen receptor (ER), offering hormone therapy as a viable treatment option. BC is a heterogeneous disease with many invasiveness-related variables, such as stage, grade, lymph node invasion, histology and hormone-receptor status. Resistance to antiestrogenic (AE) therapy remains the main problem of breast cancer treatment. In this work, the focus was on two proteins: TARDBP and BiP. TARDBP is a protein that plays important roles in transcription, pre-mRNA processing, splicing, and translation. This protein is well characterized in neurodegenerative disorders; however, little is known of its effects in BC. BiP is an endoplasmic reticulum (EndR) chaperone responsible for protein folding, calcium homeostasis and also acts as stress sensor. BiP is the primary regulator of EndR stress and exhibits antiapoptotic properties that regulate the unfolded protein response (UPR) signaling. BC therapies increase UPR signaling, hence promoting cell survival and drug resistance. The purpose of this research was to determine if BiP and TARDBP expression might be employed as predictive and prognostic indicators in luminal BC. The expression of TARDBP and BiP was analyzed in two small retrospective cohorts: cohort 1 with treatment naïve biopsies and its paired treated tumour sample; and cohort 2 with primary tumour samples and its corresponding metastasis. TARDBP expression was reduced in treated tumours relative to untreated biopsies, and this drop may be related with lower grade and increased progesterone receptor (PR) expression. BiP expression increased in metastasis compared to the primary tumour, which might be connected to the HER2 receptor. A knockdown of TARDBP was also performed, using siRNA, following treatment with tamoxifen. Regardless of treatment, cell proliferation decreased, demonstrating that this protein is essential for cell survival. To study BiP’s clinicopathological potential, complementary approaches were used: a systematic review and meta-analysis of immunohistochemistry (IHC) detection of BIP in human BC, as well as an examination of publicly accessible RNA-seq and proteomics datasets stratified by high and low quartile, were conducted. HER2, Basal-like subtypes, and greater immune score were related with elevated BiP mRNA and protein in the TCGA PanCancer dataset and CPTAC. BiP positivity was associated with worse relapse-free survival in BiP IHC meta-analysis. BiP IHC demonstrated elevated BiP expression in metastatic tumours, a correlation between BiP positivity and HER2 expression, and nuclear BiP localization as a predictor of advanced tumour stage and poor prognosis was observed. Thus, distinct methods demonstrated that BiP protein is associated with worse outcomes and may have a predictive value for BC. In conclusion, TARDBP expression is essential for cell survival and its decrease following AE therapy may be associated with less aggressive tumours. In contrast, complementary analyses of BiP reveal that BiP expression is higher in metastasis and in triple negative BC (TNBC), both associated with more aggressive tumors, suggesting that BiP is indicative of a poor prognosis. |
publishDate |
2022 |
dc.date.none.fl_str_mv |
2022-11-29T00:00:00Z 2022-11-29 2024-11-29T00:00:00Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
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info:eu-repo/semantics/masterThesis |
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masterThesis |
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http://hdl.handle.net/10773/35649 |
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eng |
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