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Molecular and functional analysis of mammary carcinogenesis related to maternal protein restriction

Grant number: 18/19432-1
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): January 01, 2019
Effective date (End): December 31, 2020
Field of knowledge:Health Sciences - Medicine - Pathological Anatomy and Clinical Pathology
Principal Investigator:Luís Fernando Barbisan
Grantee:Joyce Regina Zapaterini Rossi
Host Institution: Instituto de Biociências (IBB). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil

Abstract

Previous work has indicated that maternal protein restriction induces changes in mammary gland development and increases offspring susceptibility to induced mammary carcinogenesis after three doses of N-methyl-N-nitrosurea (MNU) in Wistar rats. Using Sprague-Dawley rats (susceptible), we will investigate the regulation networks and altered molecular pathways in the mammary gland of offspring rats subjected to maternal protein restriction and initiated with the MNU carcinogen, as well as to evaluate the administration period of the carcinogen. Pregnant females will be fed from gestational day 0 (GD0) until postnatal day 21 (PND 21, weaning) with normoprotein diet (NPD group, 17% protein) or with hypoprotein diet (HPD group, 6% protein). After weaning, the female offspring will be fed with commercial diet to the specific points of euthanasia. In PND 28 or 35, females of the NPD and HPD groups will receive a single dose of 50 mg / kg MNU and part of the females will be euthanized 24 hours after MNU application. Females of the NPD and HPD groups will also be followed up to the PND 250 to evaluate the appearance of MNU-induced mammary tumors. The onset of the first tumor will be recorded and females with tumor e 2 cm in diameter will be euthanized. The latency and mean number of tumors will be compared between NPD and HPD groups. In PND 29 or 36, the blood of animals will be collected for estrogen, progesterone and IGF-1 analysis by calorimetric methods and the abdominal mammary glands will be removed for analysis of mammary development (longitudinal and lateral diameter measurements and terminal structures), cell proliferation and apoptosis indexes, and estrogen receptor alpha expression (immunohistochemistry for Ki -67, cleaved caspase 3 and estrogen receptor-alfa), gene expression (96-genes by means of the RT-qPCR technique), and global protein expression (LC-MS / MS). Differentially expressed genes will be used for in silico analysis with breast cancer data (BRCA) from the TCGA bank. Based on the in silico results, a target gene will be selected to perform the silencing or overexpression thereof in normal mammary cells (MCF-10A) in order to analyze the viability, apoptosis, migration and invasion of these cells. At the end of the study it is expected to identify the regulatory networks and altered molecular pathways in the mammary gland of the offspring of rats submitted to maternal protein restriction and initiated with MNU carcinogen.

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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)
SARMIENTO-MACHADO, LUIS MANUEL; ROMUALDO, GUILHERME RIBEIRO; ZAPATERINI, JOYCE REGINA; TABLAS, MARIANA BAPTISTA; HENRIQUE FERNANDES, ANA ANGELICA; MORENO, FERNANDO SALVADOR; BARBISAN, LUIS FERNANDO. Protective Effects of Dietary Capsaicin on the Initiation Step of a Two-Stage Hepatocarcinogenesis Rat Model. NUTRITION AND CANCER-AN INTERNATIONAL JOURNAL, v. 73, n. 5, p. 817-828, . (18/19432-1, 16/12015-0)

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