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Functional role of PHLDA1, RET, BCAR3 and the isoform A of the progesterone receptor (PRA) in breast cancer: clinical implications


Breast cancer is a very heterogeneous group of diseases showing substantial variations in their molecular and clinical characteristics. Breast cancer is the most common cancer and the major source of morbidity and mortality among women worldwide. In Brazil, according to data from the Ministry of Health, breast cancer is the most prevalent malignancy after skin cancer and the leading cause of mortality in the female population. Besides the high incidence, the social and economic impact of the disease is enormous and makes breast cancer a major public health problem. Although we are experiencing a rapid advance in the molecular classification and the search for new therapeutic targets, routinely the treatment strategies for breast cancer is mainly based on the status of the tumor cells for steroid hormone receptors (estrogen and progesterone) and oncoprotein HER2. Identification and characterization of potential new prognostic and predictive biomarkers of response to therapy are current and important area of research in breast cancer. In addition, understanding more about the physiology and molecular biology of normal breast and pre-malignant lesions is extremely important for a better understanding of the changes associated with the tumorigenic process of the breast. This project aims to continue the functional studies exploiting results from previous projects conducted by our group on the identification and characterization of biomarkers in breast cancer. To achieve those goals three sub-projects will be developed using breast cancer models, in vitro and in vivo, using different techniques of molecular and cellular biology. The main objectives are: 1) To assess the functional role and mechanisms of actions of PHLDA1 in mammary epithelial cells and breast cancer and its potential role as a predictive factor of response to therapeutic strategies in breast cancer; 2) To characterize the expression pattern and the molecular mechanisms involved in endocrine resistance mediated by RET and BCAR3 in breast cancer; 3) To investigate the mechanisms involved in cell signaling triggered by progesterone via PRA and its contribution to the development of breast cancer. Researchers from the Faculty of Medicine of the University of São Paulo (FMUSP) and the Institute of Cancer of the State of São Paulo (ICESP), and several students (undergraduate students, master's, doctoral and post-doctoral) will participate in the present project. The expected results of the present project will generate new knowledge to improve our understanding of the role of PHLDA1, RET, BCAR3 and isoform A of the progesterone receptor (PRA) in the tumorigenic process of the breast and its use as potential biomarkers for prognosis and selection of more adequate treatment regimens for breast cancer patients. (AU)

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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)
CARLINI, MARIA JOSE; RECOUVREUX, MARIA SOL; SIMIAN, MARINA; NAGAI, MARIA APARECIDA. Gene expression profile and cancer-associated pathways linked to progesterone receptor isoform a (PRA) predominance in transgenic mouse mammary glands. BMC CANCER, v. 18, . (14/13470-8, 15/10208-3)
BONATTO, NAIELI; CARLINI, MARIA JOSE; DE BESSA GARCIA, SIMONE APARECIDA; NAGAI, MARIA APARECIDA. PHLDA1 (pleckstrin homology-like domain, family A, member 1) knockdown promotes migration and invasion of MCF10A breast epithelial cells. CELL ADHESION & MIGRATION, v. 12, n. 1, p. 37-46, . (15/10208-3)

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