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Analysis of Chaperone-Mediated autophagy (CMA) in breast tumorigenesis: impact on malignant transformation and potential use as an anticancer strategy

Grant number: 14/21382-1
Support type:Scholarships abroad - Research Internship - Post-doctor
Effective date (Start): February 02, 2015
Effective date (End): February 01, 2016
Field of knowledge:Biological Sciences - Biochemistry
Principal Investigator:Carlos Frederico Martins Menck
Grantee:Luciana Rodrigues Gomes
Supervisor abroad: Ana Maria Cuervo
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Local de pesquisa : Yeshiva University, United States  
Associated to the scholarship:11/50856-3 - Role of cellular microenvironment in molecular mechanisms of resistance to chemotherapy in a human mammary carcinoma model, BP.PD

Abstract

Autophagy is a lysosome-dependent degradation mechanism. By preventing accumulation of damaged/obsolete intracellular components and providing essential metabolic precursors, it is essential for maintenance of cellular homeostasis. Different autophagy forms have been described and demonstrated as coexisting in all cells, acting both in physiological and pathological processes. In the must well-characterized autophagic pathway, macroautophagy, cytoplasmic contents are sequestered in double-membraned vesicles (autophagosomes) and subsequently delivered to the lysosome. It is accepted that cancer cells may exploit macroautophagy as a survival mechanism against radio- and chemotherapy, facilitating tumor drug resistance. However, macroautophagy also plays tumor suppressor functions by maintenance of genome stability. Despite these recognized macroautophagy functions in tumor progression, very little is known about the Chaperone-mediated autophagy (CMA) role in cancer biology. The mainly characteristic that distinguishes CMA from other types of autophagy is its selectivity for a subset of single soluble cytosolic proteins. All CMA substrates contain a pentapeptide motif, which are selectively identified and targeted to the lysosome through the interaction with a cytosolic chaperone (hsc70). In a pioneer work, performed by Ana Maria Cuervo's group, it was verified that CMA is consistently elevated in tumors and required for optimal tumor growth and metastasis. Further, it was also reported that the lysosome-associated membrane protein type 2A (LAMP-2A), a key protein in CMA route, is overexpressed in breast tumors and related with cell survival. These data draws our attention that not only macroautophagy, but also CMA must have impact in cancer pathogenesis and treatment and, therefore, should receive larger attention in cancer research. In this context, the present work proposes to evaluate the influence of this particular type of autophagy in breast tumorigenesis, a model where macroautophagy significance has been already well-demonstrated. (AU)