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Evaluation of the functional role of intracellular and extracellular expression of PAR-4 (prostate apoptosis response-4) in the tumorigenic process of the breast: implications for chemosensitivity and potential antitumor

Grant number: 13/07035-4
Support type:Regular Research Grants
Duration: August 01, 2013 - August 31, 2015
Field of knowledge:Biological Sciences - Biochemistry - Molecular Biology
Principal Investigator:Maria Aparecida Nagai
Grantee:Maria Aparecida Nagai
Home Institution: Instituto do Câncer do Estado de São Paulo Octavio Frias de Oliveira (ICESP). Coordenadoria de Serviços de Saúde (CSS). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
Assoc. researchers:Bryan Eric Strauss

Abstract

Breast cancer is the most common cancer and the leading cause of morbidity and mortality among women worldwide. In Brazil, data from cancer registries of the Ministry of Health indicate breast cancer as the second most common malignancy and a major cause of mortality in the female population, with estimates of incidence of 52 000 new cases of breast cancer for the biennium 2012 / 2013, representing an important health problem in the country (INCA, Ministry of Health 2012; http://www.inca.gov.br). In the last two decades, various studies were conducted to identify genetic changes that could be used as markers in breast cancer, however, with few exceptions, such as the HER2, which is successfully used in the clinic, few effective biomarkers have been identified. Currently the two main areas of research in breast cancer is the discovery of new biomarkers for early diagnosis and prognosis of the disease and the understanding of critical signaling pathways involved in the carcinogenic process of the breast, which may allow the identification of new therapeutic targets and new predictive markers of tumor chemosensitivity.Several experimental evidences suggest that the PAWR (PKC apoptosis regulator WT1, also named PAR-4 Prostate apoptosis response-4) plays a central role in cell survival and has potential therapeutic selectivity for tumor cells. PAR-4 plays an important role in the intrinsic and extrinsic pathways of apoptosis, inducing apoptosis by its ability to activate the signaling pathway FADD Fas-FasL-caspase-8, to inhibit cell survival via NF-kB, which requires PAR-4 phosphorylation at residue T155 mediated by PKA, and also by its ability to down-regulate the expression of the anti-apoptotic protein Bcl-2. Endogenous PAR-4 expression is not sufficient to cause cell death, but it is essential to increase the sensitivity of most cancer cells to a second apoptotic stimulus. Par-4 protein has been shown to be secreted by normal cells or tumor cells leading to the induction of apoptosis in neighboring cells. Furthermore, in vivo studies demonstrated that transgenic animals expressing Par-4 or SAC domain of Par-4 show normal development and are resistant to cancer development, suggesting that the protein Par-4 or the SAC domain of Par-4, shows antitumor property with therapeutic potential and selectivity for tumor cells.This project aims to continue the study of the functional role of PAR-4 in breast cancer, exploiting results from previous projects developed in our lab (Process 2006/01026-0 and 2010/16543-5). To achieve these goals five sub-projects will be developed using a model of breast cancer in vitro and in vivo, using different techniques of molecular and cellular biology. The main objectives are: 1) to validate the role of Par-4, intracellular and secreted in survival and chemosensitivity in different breast cancer cells in culture, 2) to investigate the role of Par-4 in the microenvironment and cancer cells in breast tumor formation and chemosensitivity to docetaxel and 5-fluorouracil; 3) to identify potential binding sites for the tumor suppressor gene PAR-4 cells in breast cancer using the technique of Chip-Seq, 4) perform a pilot study for the construction and characterization of potential antitumor adenoviral vector containing the SAC domain of Par-4; and 5) to identify the occurrence of PAR-4 mutations in breast tumors using new generation sequencing technique. Researchers from the Faculty of Medicine of the USP (FMUSP) and the Institute of Cancer of São Paulo (ICESP) and several students will participate in the present project.The expected results of the present project will generate new knowledge to improve our understanding of the molecular bases of the tumorigenic process of the breast and molecular characterization of the potential of Par-4 as biomarker for diagnosis, prognosis and selection for the application of novel therapeutics strategies for breast cancer patients. (AU)

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
DE ALCANTARA FILHO, PAULO R.; MANGONE, FLAVIA R.; PAVANELLI, ANA C.; DE BESSA GARCIA, SIMONE A.; NONOGAKI, SUELY; DE TOLEDO OSORIO, CYNTHIA A. B.; DE ANDRADE, VICTOR P.; NAGAI, MARIA A. Gene expression profiling of triple-negative breast tumors with different expression of secreted protein acidic and cysteine rich (SPARC). BREAST CANCER MANAGEMENT, v. 7, n. 2 MAY 2018. Web of Science Citations: 0.
DE BESSA GARCIA, SIMONE APARECIDA; PAVANELLI, ANA CAROLINA; CRUZ E MELO, NATALIA; NAGAI, MARIA APARECIDA. Prostate apoptosis response 4 (PAR4) expression modulates WNT signaling pathways in MCF7 breast cancer cells: A possible mechanism underlying PAR4-mediated docetaxel chemosensitivity. International Journal of Molecular Medicine, v. 39, n. 4, p. 809-818, APR 2017. Web of Science Citations: 5.

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