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Role of chaperone-mediated autophagy in breast cancer

Abstract

Autophagy is a lysosome-dependent degradation process essential for maintenance of cellular homeostasis. Based on the mechanism used for substrate delivery into the lysosome lumen, autophagy is classified in: macroautophagy (MA), microautophagy (MI) and chaperone-mediated autophagy (CMA). Unlike MA and MI, CMA is a selective type of autophagy in which proteins are identified and transported one-by-one by a cytosolic chaperone. Dysfunctional autophagy is correlated to several human disorders, including cancer. The MA relevance in cancer is well-established, but CMA still very little explored. Among the different types of cancer, breast cancer stands out because, besides being the most frequent, it is the second leading cause of cancer related death among worldwide women. Estrogen is the etiological factor of breast cancer, and therefore, it is central for the genesis and progression of breast tumors. Consequently, therapies based on modulating the cellular response to this hormone are the main tool for treating breast tumors. In this context, the present project intends to study the effect of CMA on cellular estrogen response to evaluate its potential implication in breast cancer biology. To this end, the role of CMA in the cellular response to 17²-estradiol in both normal and breast tumor cells will be evaluated to investigate its potential effect on malignant transformation and treatment of breast cancer, respectively. Regarding the role of CMA in the initiation of breast tumors, firstly, it will be evaluated possible changes in the frequency of estrogen-mediated induction of malignant transformation in CMA-proficient and -deficient cells, submitted to long periods of exposure to this hormone. Further, it will be explored the potential molecular mechanisms responsible for these CMA-mediated changes in transformation capacity, such as changes in cellular metabolism. The CMA substrates involved in this process will be identified by comparative proteomics of lysosomes and their role in malignant transformation will be later validated. Another important objective of this project will be to investigate the potential implication of CMA in breast tumor cells response to hormone therapy. Thus, in addition to revealing the latent involvement of CMA in the early stages of breast cancer development, this research project has potential translational value and may support the use of modulators of CMA activity as a future anticancer strategy. (AU)

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