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Hippo-YAP as a converging pathway for biochemical and mechanical signals from the extracellular matrix during mammary gland morphogenesis and breast cancer progression


Cell behavior and tissue homeostasis are not exclusively controlled by soluble chemical signals. Microenvironmental factors such as the extracellular matrix (ECM) arrangement, tissue architecture and mechanical forces are sources of signals capable of determining a cell's fate. Hippo-YAP (Hippo is a cascade of kinases that inactivate YAP, which is a transcription co-activator) regulates organ growth and size, and acts in mesenchymal stem cells as a sensor for mechanical signals from the microenvironment. Bioinformatics analysis of transcriptomes indicate the YAP-regulated genes are differentially expressed during mammary gland development and breast cancer progression. Preliminary results suggest that laminin-111 (LN1), an ECM protein that induces functional differentiation in the mammary epithelia, reduces nuclear YAP in non-malignant cells. Therefore, my hypothesis is that Hippo-YAP could be involved in the controlled tissue growth and quiescence of mammary gland, that LN1 and microenvironment viscosity influence Hippo-YAP and that these processes could be defective in breast cancer. I will use physiologically relevant assays of 3D culture that mimics branching morphogenesis of mammary epithelia and breast cancer progression in combination with molecular biology, biochemistry, bioinformatics and microscopy approaches. My prediction is that the conclusion of this project will bring details of the regulation of cell proliferation and invasion which are hallmarks of cancer progression, and that this information may be used to improve diagnosis, prognosis and treatment of cancer. (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)
GOMES, LUCIANA RODRIGUES; REILY ROCHA, CLARISSA RIBEIRO; MARTINS, DAVI JARDIM; PETISCO FIORE, ANA PAULA ZEN; KINKER, GABRIELA SARTI; BRUNI-CARDOSO, ALEXANDRE; MARTINS MENCK, CARLOS FREDERICO. ATR mediates cisplatin resistance in 3D-cultured breast cancer cells via translesion DNA synthesis modulation. CELL DEATH & DISEASE, v. 10, JUN 12 2019. Web of Science Citations: 4.
ZEN PETISCO FIORE, ANA PAULA; RIBEIRO, PEDRO DE FREITAS; BRUNI-CARDOSO, ALEXANDRE. Sleeping Beauty and the Microenvironment Enchantment: Microenvironmental Regulation of the Proliferation-Quiescence Decision in Normal Tissues and in Cancer Development. FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY, v. 6, JUN 7 2018. Web of Science Citations: 5.
FIORE, ANA PAULA ZEN PETISCO; SPENCER, VIRGINIA A.; MORI, HIDETOSHI; CARVALHO, HERNANDES F.; BISSELL, MINA J.; BRUNI-CARDOSO, ALEXANDRE. Laminin-111 and the Level of Nuclear Actin Regulate Epithelial Quiescence via Exportin-6. CELL REPORTS, v. 19, n. 10, p. 2102-2115, JUN 6 2017. Web of Science Citations: 14.

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