• JoomlaWorks Simple Image Rotator
  • JoomlaWorks Simple Image Rotator
  • JoomlaWorks Simple Image Rotator
  • JoomlaWorks Simple Image Rotator
  • JoomlaWorks Simple Image Rotator
  • JoomlaWorks Simple Image Rotator
  • JoomlaWorks Simple Image Rotator
  • JoomlaWorks Simple Image Rotator
  • JoomlaWorks Simple Image Rotator
  • JoomlaWorks Simple Image Rotator
 
  Bookmark and Share
 
 
Master's Dissertation
DOI
https://doi.org/10.11606/D.5.2020.tde-27102020-153855
Document
Author
Full name
Renan Gomes do Nascimento
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2020
Supervisor
Committee
Nagai, Maria Aparecida (President)
Camillo, Cláudia Malheiros Coutinho
Diz, Maria Del Pilar Estevez
Maria, Durvanei Augusto
Title in Portuguese
Avaliação do perfil de expressão imuno-histoquímica dos membros da família PHLDA (Pleckstrin homology like domain family A) e potencial valor prognóstico em câncer de mama
Keywords in Portuguese
AKT
Biomarcadores
Imuno-histoquímica
Neoplasia da mama
PHLDAs
Resposta endócrina
Abstract in Portuguese
Apesar dos avanços na classificação molecular do câncer de mama, nossa compreensão da fisiopatologia da doença ainda é limitada, principalmente devido à considerável heterogeneidade intratumoral. Assim, centenas de outros candidatos a biomarcadores vêm sendo investigados e estudados para possíveis implicações no diagnóstico, prognóstico e terapia personalizada. Nesse contexto, os membros da família PHLDA (Pleckstrin homology like domain family A), composta por três genes localizados em diferentes cromossomos: PHLDA1 (12q21.2), PHLDA2 (11p15.4) e PHLDA3 (1q32.1) estão sob investigação por diferentes grupos de pesquisa como potenciais biomarcadores em vários tipos de câncer. Foi relatado que a expressão alterada desses genes está envolvida no processo tumorigênico. No entanto, o valor prognóstico e preditivospreditivo das proteínass de PHLDA1, 2 e 3 no câncer de mama ainda não foi definido. Portanto, neste estudo, procuramos determinar o padrão de expressão proteica dos membros da família PHLDA por imuno-histoquímica (IHQ) em uma grande coorte de amostras de pacientes com câncer de mama luminal e estimar o valor prognóstico potencial desses candidatos a biomarcadores. Este estudo foi baseado em uma coorte de conveniência composta de 493 amostras de tumores primários de mama do subtipo luminal, divididos em cinco blocos de TMA (Tissue Microarray) para a avaliação IHQ da expressão proteica dos integrantes da família PHLDA. Todas as análises quantitativas de PHLDA1, PHLDA2 e PHLDA3 foram avaliadas e pontuadas em células tumorais pelo software de patologia digital QuPath. No final, as amostras foram categorizadas em dois grupos (negativo e positivo ou low e high), com base nos valores calculados de células tumorais positivas para cada marcador do estudo, e esses dados foram correlacionados com características demográficas, clinico-patológicas e de sobrevida das pacientes. A avaliação IHQ revelou que a expressão de PHLDA1 e PHLDA2 foi identificada predominantemente no citoplasma de células tumorais da mama, enquanto isso, PHLDA3 apresentou prevalente imunorreatividade nuclear e perinuclear, e menos frequentemente citoplasmática. Na população avaliada não foram observadas diferenças significativas entre a exprressão dos membros da família PHLDA e a sobrevida das pacientes. Entretanto, nossa avaliação IHQ apoiada por análises de banco de dados, mostrou que a expressão diferencial dos integrantes da família PHLDA podem estar associados com a resposta ao tratamento anti-hormonal. Embora preliminares, nossos achados sugerem que a expressão de PHLDA2 e PHLDA3 pode ter um valor preditivo de resposta à terapia endócrina em pacientes com câncer de mama do subtipo luminal. Os resultados deste trabalho fornecem informações importantes sobre o papel dos membros da família PHLDA na tumorigênese da mama e o impacto na sobrevida e na resposta à terapia endócrina das pacientes com câncer de mama
Title in English
Evaluation of the immunohistochemical expression profile of PHLDA (Pleckstrin homology like domain family A) and potential prognostic value in breast cancer
Keywords in English
AKT
Biomarkers
Breast cancer
Endocrine response
Immunohistochemistry
PHLDAs
Abstract in English
Despite advances in the molecular classification of breast cancer, our understanding of the pathophysiology of the disease is still limited, mainly due to the considerable intratumoral heterogeneity. Thus, hundreds of other candidates for biomarkers have been investigated and studied for possible implications for diagnosis, prognosis and personalized therapy. In this context, the members of the PHLDA family (Pleckstrin homology like domain family A), composed of three genes located on different chromosomes: PHLDA1 (12q21.2), PHLDA2 (11p15.4) and PHLDA3 (1q32.1) are under investigation by different research groups as potential biomarkers in various types of cancer. It has been reported that the altered expression of these genes is involved in the tumorigenic process. However, the prognostic value of mRNA and PHLDA1, 2 and 3 proteins in breast cancer has not yet been defined. Therefore, in this study, we sought to determine the pattern of protein expression of the PHLDA family members by immunohistochemistry (IHC) in a large cohort of samples from patients with luminal breast cancer and to estimate the potential prognostic value of these candidates for biomarkers. This study was based on a convenience cohort composed of 493 samples of primary breast tumors of the luminal subtype, divided into five blocks of TMA (Tissue Microarray) for the IHC assessment of the protein expression of the members of the PHLDA family. All quantitative analyzes of PHLDA1, PHLDA2 and PHLDA3 were evaluated and scored on tumor cells by the digital pathology software QuPath. In the end, the samples were categorized into two groups (negative and positive or low and high), based on the calculated values of positive tumor cells for each marker in the study, and these data were correlated with demographic, clinical-pathological and patient survival characteristics. The IHQ evaluation revealed that the expression of PHLDA1 and PHLDA2 was identified predominantly in the cytoplasm of breast tumor cells, meanwhile, PHLDA3 showed prevalent nuclear and perinuclear immunoreactivity, and less frequently cytoplasmic. Here, no significant differences were observed between the expression of the PHLDA family members and the patients' survival. However, our IHC assessment, supported by database analyzes showed that the differential expression of the members of the PHLDA family might be associated with the response to anti-hormonal treatment. Although preliminary, our findings suggest that the expression of PHLDA2 and PHLDA3 may have a predictive value for response to endocrine therapy in patients with luminal subtype breast cancer. The results of this work provide valuable information about the role of members of the PHLDA family in breast tumorigenesis and the impact on survival and response to endocrine therapy in patients with breast cancer
 
WARNING - Viewing this document is conditioned on your acceptance of the following terms of use:
This document is only for private use for research and teaching activities. Reproduction for commercial use is forbidden. This rights cover the whole data about this document as well as its contents. Any uses or copies of this document in whole or in part must include the author's name.
Publishing Date
2020-10-27
 
WARNING: Learn what derived works are clicking here.
All rights of the thesis/dissertation are from the authors
CeTI-SC/STI
Digital Library of Theses and Dissertations of USP. Copyright © 2001-2021. All rights reserved.